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Pleiotropic AT₁ Receptor Signaling Pathways Mediating Physiological and Pathogenic Actions of Angiotensin II

Department of Physiology (L.H.), Faculty of Medicine, Semmelweis University, H-1444 Budapest, Hungary; and Endocrinology and Reproduction Research Branch (K.J.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510

Address correspondence and requests for reprints to: Kevin J. Catt, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, Building 49, Room 6A36, National Institutes of Health, Bethesda, Maryland, 20892-4510. E-mail: cattk{at}mail.nih.gov.

	ABSTRACT

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 
Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT₁ receptor (AT₁R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT₁R activation via G_q/11 stimulates phospholipases A₂, C, and D, and activates inositol trisphosphate/Ca²⁺ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-B pathway. The AT₁R also signals via G_i/o and G_11/12 and stimulates G protein-independent signaling pathways, such as ß-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT₁R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT₁R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT₁R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT₁R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II’s pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT₁R antagonists, in addition to their established therapeutic actions in essential hypertension.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 
THE EXISTENCE OF the renin-angiotensin system (RAS) was recognized more than 100 yr ago, after the discovery of renin by Tigerstedt and Bergman (1). Angiotensin II, the octapeptide hormone that mediates most of the known biological actions of the RAS, was isolated in 1940 by Braun-Menendez et al. (2) and Page and Helmer (3). The action of renin on its substrate, angiotensinogen, generates the inactive decapeptide, angiotensin I, which is hydrolyzed by angiotensin-converting enzyme (ACE) to the potent pressor octapeptide, angiotensin II (Ang II). The RAS was initially regarded as an endocrine system in which circulating Ang II regulates blood pressure and electrolyte balance via its actions on vascular tone, aldosterone secretion, renal sodium handling, thirst, water intake, sympathetic activity, and vasopressin release. The cellular Ang II receptor was identified in 1974 as a high-affinity plasma membrane-binding site that is sensitive to guanyl nucleotides (4). Later, distinct AT₁ and AT₂ receptor subtypes were identified by selective ligands (5) and were subsequently characterized as seven transmembrane receptors by molecular cloning (6, 7, 8, 9). The G protein-coupled AT₁R mediates the known physiological and pathological actions on Ang II and undergoes rapid desensitization and internalization after agonist stimulation. In contrast, the AT₂ receptor does not exhibit the latter features and acts mainly through G_i and tyrosine phosphatases to exert predominantly inhibitory actions on cellular responses mediated by the AT₁R and growth factor receptors (10).

Recent studies using gene targeting to delete or enhance specific components of the RAS have confirmed its physiological roles and its novel functions in the development and maintenance of renal vascular and papillary structure (11, 12, 13). They have also highlighted the importance of paracrine and autocrine effects of local RAS in several tissues. Clinical trials using ACE inhibitors and AT₁R blockers have shown that the actions of this system extend far beyond blood pressure control (14). It has become clear that the deleterious actions of local RAS on cardiovascular remodeling and renal function account for the beneficial effects of these agents in patients with hypertension, left ventricular hypertrophy, heart failure, and diabetic nephropathy (14). The RAS has also been proposed to exert intracrine effects due to the intracellular formation of Ang II (15, 16). However, kinetic studies suggest that intracellular Ang II is largely derived from receptor-mediated uptake of the extracellular peptide (17).

Animal models and clinical data have also helped to establish that inhibition of Ang II action in nonclassical target sites, such as immune cells, explains some of the unanticipated therapeutic effects of ACE inhibitors and AT₁R blockade (14). Parallel studies on the molecular mechanism of action of Ang II have revealed that its main target, the AT₁R, is one of the most versatile members of the G protein-coupled receptor (GPCR) family. Ang II exerts several cytokine-like actions via the AT₁R and can stimulate multiple signaling pathways, transactivate several growth factor receptors, and promote the formation of reactive oxygen species (ROS) and other proinflammatory responses. Furthermore, recent evidence indicates that the AT₁R may serve as a "stretch sensor" because mechanical stress can activate the AT₁R without the involvement of Ang II (18, 19). Many of these effects are highly cell specific, and numerous studies are currently under way to identify the roles of these signaling pathways in the physiological and pathophysiological actions of Ang II. This review focuses on the implications of recent findings on the Ang II-induced signaling pathways and functions of the AT₁R, which mediates the main physiological and pathological effects of the RAS. The biological actions and signaling mechanisms of AT₂ receptors, Ang IV and Ang(1–7) are described in recent reviews (10, 20, 21, 22).

	THE RENIN-ANGIOTENSIN SYSTEM

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 
The classical RAS is an enzymatic cascade initiated by the cleavage of circulating angiotensinogen by renin, an aspartyl protease, to form the decapeptide angiotensin I (Fig. 1). Angiotensin I is further cleaved by ACE, a dipeptidyl carboxypeptidase, to produce the circulating Ang II octapeptide that is the main effector hormone of the RAS. The ectoenzyme, ACE, is expressed at the surface of endothelial cells, where it catalyzes the conversion of Ang I to Ang II. ACE also cleaves and inactivates bradykinin and thus contributes to the therapeutic effects (and side-effects) of ACE inhibitors. The ACE gene has an insertion/deletion polymorphism in which a 287-bp deletion in intron 16 (ACE-D) leads to increased tissue and circulating levels of the mutant enzyme. This deletion has been reported to be a risk factor for certain cardiovascular and renal diseases and the progression of sarcoidosis (23, 24).

View larger version (25K): [in this window] [in a new window]   Fig. 1. The Main Components of the RAS The classical cascade and recently discovered alternative pathways for Ang II generation are shown. CAGE, Chymostatin-sensitive Ang II-generating enzyme; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; t-PA, tissue plasminogen activator.

Ang II can be further metabolized by aminopeptidase A to form Ang III [Ang(2–8)] and then by aminopeptidase N to Ang IV [Ang(3–8)]. Ang II and III exert their effects via the AT₁R and AT₂R. Ang IV is also a biologically active peptide with low affinity for AT₁R and AT₂R and acts in the brain on insulin-regulated aminopeptidase. This protein is a transmembrane metalloprotease that cotranslocates in vesicles with glucose transporter 4 to the cell surface in response to insulin (29). Ang IV and the endogenous ligand, LVV-hemorphin 7, which are potent inhibitors of insulin-regulated aminopeptidase, enhance memory and learning and reverse memory deficits in amnesic animals (30). A recently identified second form of ACE (ACE-2) and other endopeptidases can cleave Ang I to produce Ang(1–7), which has vasodilator and cardioprotective effects (22). Ang(1–7) lacks the C-terminal phenylalanine⁸ residue of Ang II that is critical for binding and activation of AT₁Rs, and has been proposed to act via another GPCR, putatively the mas oncogene (31).

	BIOLOGICAL ROLES OF LOCAL Ang II FORMATION IN TARGET TISSUES

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 
The beneficial effects of ACE inhibitors and AT₁R blockers on the morbidity and mortality of patients with cardiovascular diseases are at least partially independent of the blood pressure-lowering effects of these drugs (14, 32, 33). Furthermore, such effects are also observed in patients with low renin hypertension (34), and the pharmacokinetic properties of ACE inhibitors suggest that their principal actions occur at tissue sites (35). Discrepancies between the circulating renin and Ang II levels, and the results of clinical studies with drugs that inhibit the RAS, have indicated the importance of local Ang II formation in various tissues (13, 17). Moreover, the functions of the tissue and systemic RAS activities show significant differences. The circulating Ang II concentration is relatively low (10–50 pM) and, even in pathological situations, rarely reaches the level required for 50% saturation of the AT₁R (26). However, classical Ang II target tissues, such as adrenal glomerulosa cells and vascular smooth muscle cells (VSMCs), contain abundant AT₁Rs and exhibit adequate intracellular signaling to activate biological responses at the relatively low levels of receptor occupancy that pertain at circulating hormone levels. Furthermore, in many tissues the locally formed Ang II levels are much higher than the plasma concentration (17) and can elicit significant biological responses in cells with relatively low levels of AT₁R expression. Thus, the importance of the nonclassical Ang II target tissues is particularly relevant when the local generation of the peptide is sufficiently high.

	CLASSICAL G PROTEIN-MEDIATED SIGNALING MECHANISMS

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 
The AT₁R is a typical heptahelical GPCR and, on agonist binding, elicits multiple cellular responses, predominantly via coupling to G_q/11, and also to G_12/13 proteins, and G_i/o in rodents (5). G_q/11-mediated inositol phosphate/Ca²⁺ signaling is the primary transduction mechanism initiated by Ang II in its major physiological target tissues, including adrenal, neuronal, cardiac, renal, and smooth muscle cells (5). The pathophysiological importance of this pathway for Ang II-induced hypertension and cardiac hypertrophy was demonstrated in mice expressing a C-terminal G_q peptide that inhibits receptor/G_q/11 interaction (36). The AT₁R can also couple to pertussis toxin-sensitive G_i/o proteins that inhibit adenylyl cyclase in some target tissues (e.g. rat adrenal glomerulosa, liver, kidney, and pituitary cells) (5). In adrenocortical cells, G_i/o-mediated actions of Ang II also contribute to its regulatory actions on voltage-sensitive T- and L-type Ca²⁺ channels (26, 37, 38, 39). Another important mechanism is activation of the G_11/12 family of G proteins, which contribute to the physiological actions of Ang II by mediating its activation of phospholipase C (PLC) and phospholipase D, L-type Ca²⁺ channels, and Rho kinase (40, 41, 42, 43). Ang II-induced stimulation of cAMP responses has also been reported, but this results from activation of Ca²⁺-sensitive adenylyl cyclases or calcineurin, a Ca²⁺-dependent phosphatase, rather than receptor coupling to G_s (44).

In addition to its rapid, G protein-mediated actions via second messengers and their pathways, Ang II activates secondary responses that are typically associated with stimulation of growth factor receptors, and regulate cell growth, proliferation, cell migration, apoptosis, and gene expression. These effects are often the consequence of Ang II-induced activation of cytoplasmic tyrosine kinases such as Pyk2, c-Src, Tyk2, FAK, Janus kinase 2 (Jak2), and transactivation of membrane-associated growth factor receptor tyrosine kinases (45, 46). Ang II-induced cytoplasmic Ca²⁺ signaling and protein kinase C (PKC) activation regulate the activities of Src, FAK, and Pyk2 (46). Activation of heterotrimeric G proteins by the AT₁R also releases their ß-subunits, which can cause further activation of tyrosine kinases (47, 48). At least one tyrosine kinase (Jak2) has been shown to interact directly with a tyrosine-containing motif in the cytoplasmic tail of the AT₁R (49).

Tyrosine phosphorylation of receptors and scaffold proteins, such as growth factor receptors, integrins, GPCR kinase-interacting protein 1 (GIT1) and p130Cas, paxillin, tensin, vinculin, Grb2 and other adapters, is an important factor in the organization of signaling pathways (46, 50). For example, PLC is constitutively associated with GIT1, a GPCR kinase-interacting protein, and Ang II-induced, Src-mediated tyrosine phosphorylation of GIT1 leads to its activation (51). Although Ang II-induced stimulation of inositol triphosphate signaling is primarily caused by G protein-mediated activation of PLCß isoenzymes, tyrosine kinase-regulated activation of PLC also makes a significant contribution to this process in certain cell types (e.g. VSMCs) (5). In addition, GIT1 can serve as a scaffold protein to facilitate Ang II- and epidermal growth factor (EGF)-induced activation of MEK (MAPK kinase 1) and ERK (52). A recent study suggests that GIT1 is a scaffold for ERK1/2 activation in focal adhesions and regulates cell migration in VSMCs and other cells (53). Another recently identified, Src-regulated scaffold protein is p130Cas, which associates with focal adhesions and regulates the migration of smooth muscle cells via activation of c-Jun NH₂-terminal kinase (JNK) (50).

Ang II is a potent stimulus of smooth muscle growth and migration and extracellular matrix formation in the vascular system (54). It stimulates the proliferation of human cerebral artery VSMCs through a basic fibroblast growth factor-dependent pathway, but causes hypertrophy without proliferation in VSMCs from peripheral arteries (55). Ang II also stimulates the proliferation of cultured human mesangial cells through activation of MAPKs, specifically JNK (56), and of IEC-18 intestinal epithelial cells via transactivation of the EGF receptor (EGFR) and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin/p70S6K1 signaling pathway (57). In adrenal glomerulosa cells, for which Ang II acts as a trophic factor in vivo as well as a stimulus to aldosterone secretion, variable effects on growth and proliferation have been observed in vitro, in some cases with stimulation via calcineurin and MAPK (58). However, a recent report indicates that Ang II stimulates protein synthesis but inhibits proliferation in cultured rat adrenal glomerulosa cells (59). In the testis, Ang II stimulates contraction and growth of the peritubular myoid cells, apparently via MAPK and tyrosine phosphorylation (60). In the skin, activation of AT₁R signaling promotes wound healing by stimulating the growth of keratinocytes and myofibroblasts (61).

In many tissues, stimulation by Ang II leads to MAPK activation by transactivating growth factor receptors, including EGF, platelet-derived growth factor, and IGF receptors, and Axl (62, 63, 64), but in some cells [e.g. human embryonic kidney (HEK) 293 cells], PKC activation can directly activate the pathway leading to ERK activation (65) (Fig. 2). Transactivation of the EGFR and other growth factor receptors is an important component of AT₁R-mediated signaling via MAPK pathways in cardiac and smooth muscle cells. This transactivation pathway is mediated by Ca²⁺, PKC, and Src-dependent transactivation of transmembrane matrix metalloproteases, which cause release of heparin-binding EGF from its precursor in the cell membrane and activation of the EGFR (66, 67, 68). In hepatic C9 cells Ang II-induced activation of endogenous AT₁Rs mediates ERK1/2 activation by a similar mechanism (65, 69, 70). In C9 cells, agonist activation of endogenous AT₁R and EGFR induced the caveolin-dependent formation of a multireceptor complex containing both the AT₁R and the transactivated EGFR. Conversely, activation of EGFR caused phosphorylation, internalization, and desensitization of AT₁Rs, via a PLC, PI3K-, and PKC-mediated mechanism (71) (Fig. 2).

View larger version (49K): [in this window] [in a new window]   Fig. 2. Ang II-induced, G Protein-Mediated Signaling Pathways Leading to ERK1/2 Activation MMP, Matrix metalloproteinase; HB-EGF, heparin-binding EGF; MEK, MAPK kinase; RSK, p90 ribosomal S6 kinase. [Modified from B. H. Shah et al.: Mol Endocrinol 18:035–2048, 2004 (Ref. 65 ) with permission from The Endocrine Society.]

	G PROTEIN-INDEPENDENT EFFECTS OF Ang II

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 
Activation of MAPKs
The agonist-activated AT₁R can also stimulate G protein-independent signal transduction mechanisms by directly associating with signaling molecules, such as ß-arrestins and tyrosine kinases (Fig. 3). Arrestins were initially defined as molecules that bind to agonist-activated and phosphorylated GPCRs and cause homologous desensitization of these receptors by uncoupling them from their cognate G proteins. Like many other activated GPCRs, the AT₁R binds ß-arrestins, which have clathrin and activator protein (AP) 2 adapter-binding domains that target them to endocytosis via clathrin-coated vesicles. Recent studies also demonstrated that ß-arrestins can also serve as scaffold proteins that organize signaling complexes for the activation of MAPKs (73, 74, 75, 76, 77). As in other GPCRs, activation of the AT₁R leads to its phosphorylation by specific receptor kinases and binding of ß-arrestin, which uncouples it from G proteins and also serves as an adaptor for clathrin-mediated internalization. The AT₁R belongs to the class B group of GPCRs, which bind ß-arrestins tightly due to the presence of a defined serine-threonine-leucine motif (78, 79) in their cytoplasmic tail (80, 81). This tight binding causes ß-arrestin to remain associated with the receptor during its internalization into endosomes (77). ß-Arrestins also serve as scaffolds to organize the formation of signaling complexes (74) that mediate AT₁R-mediated activation of ERK and JNK3 MAPKs (77). Studies on a mutant AT₁R that cannot couple to G proteins have shown that ß-arrestin2-mediated ERK activation can occur in the absence of G protein activation (82). Although the biological role of this process has not been defined, it could promote the phosphorylation of cytosolic targets of ERK, which when activated by this mechanism cannot enter the nucleus due to their association with the receptor, and are mostly located on the surface of endosomes (74). Studies on PAR2 receptors have shown that ß-arrestin-mediated MAPK activation does not stimulate DNA synthesis or cell division but can promote reorganization of the actin cytoskeleton and chemotaxis and may contribute to migration of cancer cells (83, 84, 85). A recent report suggests that Ang II can also induce chemotaxis by a G protein-independent, ß-arrestin-mediated mechanism (86). Additional studies are needed to elucidate the exact biological function(s) of these mechanisms after AT₁R activation.

View larger version (42K): [in this window] [in a new window]   Fig. 3. Ang II-Stimulated AT1Rs Also Activate G Protein-Independent Signaling Pathways

Studies with another mutant AT₁R, with deletions of Ala²²¹ and Leu²²², suggest that Ang II-induced, Cdc42-mediated activation of JNK can occur in a mutant receptor that is unable to activate G_q-mediated signaling (90, 91). The latter mutant was also able to stimulate Rap1-dependent ERK1/2 activation, but the physiological relevance of this pathway needs further studies because it was not activated by the wild-type receptor.

Activation of the Jak/Signal Transducer and Activator of Transcription (STAT) Signaling Pathway
In cardiac fibroblasts, aortic smooth muscle cells, and the kidney, Ang II-induced AT₁R activation also stimulates the Jak/STAT pathway (Fig. 3), a characteristic signal transduction mechanism of cytokine receptors (5). This pathway has been linked to several of the pathophysiological effects of Ang II, including cardiac hypertrophy, dysfunction and heart failure (92), vascular inflammation and smooth muscle cell growth (93), and renal tubulointerstitial fibrosis (94). Jak/STAT activation also provides a positive feedback pathway by up-regulating angiotensinogen formation, leading to increased production of Ang II (95). The ability of cyclical stretch to induce matrix metalloproteinase expression in cardiac myocytes is also mediated by the Ang II-Jak/STAT pathway (96).

However, Ang II exerts both direct and indirect actions on the Jak/STAT pathway because AT₁R activation also causes the release of IL-6 and other cytokines that stimulate this pathway. Although Ang II clearly serves as a proinflammatory mediator by acting on VSMCs and endothelial cells, and also by directly activating macrophages and other immune cells, the exact role of Ang II-induced activation of the Jak/STAT pathway in immune cells has not yet been defined.

Janus kinases (Jaks) are cytoplasmic tyrosine kinases initially identified as essential components of interferon receptor signaling (97). The Jak family includes three ubiquitously expressed members (Jak1, Jak2, and Tyk2) and Jak3, which is expressed primarily in hematopoetic cells. During cytokine stimulation, activation of Jak kinases leads to tyrosine phosphorylation and activation of STAT proteins, which dimerize and translocate to the nucleus to regulate the expression of target genes. The Jak/STAT signal transduction pathway can also be activated by GPCRs, and Ang II-mediated activation of STAT1–3, STAT5, and STAT6 has been reported (92, 98, 99). The exact roles of the individual STAT proteins are currently under investigation, and it appears that activation of STAT1 and STAT3 in cardiac cells exerts opposing biological actions by inducing 1) apoptosis, proinflammatory, and antiproliferative mechanisms; and 2) cardioprotective, mostly antiinflammatory and growth-stimulatory responses, respectively (92). Interestingly, most of these GPCRs, including receptors for Ang II, thrombin, chemokines, and platelet activating factor, are found on the surface of blood cells, where the Jak/STAT pathway has a major role in cytokine signal transduction. In VSMCs, the AT₁R activates Jak2 via its association with a YIPP motif in the C-terminal tail of the receptor (49). The same motif is required for PLC- activation (100) and possibly for EGFR transactivation (101), and optimal binding of the AT₁R (102). Studies in VSMCs have suggested that Ang II-induced tyrosine phosphorylation of Jak2 is G protein mediated, because it is dependent on increased cytoplasmic Ca²⁺ concentration and activation of PKC (103). However, other studies with mutant receptors indicate that the AT₁R can also activate the Jak/STAT pathway via G protein-independent mechanisms. Substitutions of five carboxyl-terminal tyrosine residues (Tyr292, Tyr302, Tyr312, Tyr319, and Tyr339) with phenylalanine, and substitution of Asp74 with glutamic acid, led to mutant AT₁Rs that were unable to activate G_q, but could induce tyrosine phosphorylation and activation of Jak2 and its effector, STAT1 (104). Such activation of the Jak/STAT pathway could stimulate cell growth in the absence of G_q-mediated signaling (104). These data suggest that the AT₁R can regulate intranuclear targets via the Jak/STAT pathway in the absence of G protein activation.

AT₁R-Associated Proteins
The C-terminal cytoplasmic domain of GPCRs binds to a variety of intracellular proteins involved in receptor signaling, desensitization, and endocytosis. These include proteins such as GRKs and ß-arrestins, and receptor-specific proteins that bind to individual receptors or classes thereof. Those associated with the AT₁R include PLC- and Jak proteins (49, 100), and novel proteins found by two-hybrid studies, including AT₁R-associated protein (ATRAP) (105), Ang II receptor-associated protein 1 (ARAP-1) (106), EP24.15 (EC 3.4.24.15, thimet oligopeptidase) (107), and GLP, a GDP/GTP exchange factor-like protein (108). PLC- and Jak2 kinase [the latter possibly via Src homology phosphatase 2 (SHP-2) as an adaptor] have been found to associate with the YIPP sequence in the proximal region of the cytoplasmic domain (49, 100). ATRAP is an 18-kDa protein with three N-terminal transmembrane domains and interacts specifically with the C-terminal region of the AT₁R (105). Endogenous and transfected ATRAP is located in the plasma membrane and within intracellular compartments including endoplasmic reticulum, Golgi, and endocytic vesicles (109). Furthermore, it is associated with the AT₁R at both sites and appears to influence receptor endocytosis and function in diverse cell types. In cardiomyocytes, overexpression of ATRAP reduces cell surface AT₁Rs, as well as Ang II-induced signaling and protein synthesis (110). ARAP-1 is a less well-characterized 57-kDa protein that may have a role in AT₁R recycling to the plasma membrane (106).

An interesting and recently identified AT₁R-associated protein is the novel 531-residue protein termed GLP, which stimulates hypertrophic responses when expressed in VSMCs and immortalized renal proximal tubule cells (108). The AT₁R also associates with caveolin in smooth muscle cells, and this has been proposed to coordinate Ang II-induced signaling (111). Other studies have suggested that a caveolin-binding-like motif in the receptor’s cytoplasmic tail has an important role in the recycling of internalized AT₁Rs to the plasma membrane (112). Recently, caveolin was found to be essential for Ang II-stimulated targeting of the AT₁R into lipid rafts and activation of Rac1, and subsequent ROS-mediated hypertrophic responses in VSMCs (113).

	MODULATION OF AT1R FUNCTION BY HOMO- AND HETERODIMERIZATION

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Recent studies using fluorescence or bioluminescence resonance energy transfer have demonstrated that many GPCRs exist in the cell as dimers or oligomers. Although the stoichiometry of this process (i.e. dimers or oligomers) is difficult to assess with these biophysical techniques, a recent study on the organization of rhodopsin using atomic force microscopy suggest that rhodopsin-related, family A GPCRs, such as the AT₁R, exist in dimers that may be further arranged into oligomeric arrays (114). Homo- and heterodimerization of several GPCRs have been reported (115). The biological function of this process is most evident for family C GPCRs, where heterodimerization is required for proper targeting of newly synthesized receptors to the cell surface.

Agonist-independent homodimerization of transiently expressed AT₁Rs has been detected by bioluminescence resonance energy transfer studies in transfected COS-7 cells, in which dimerization of the receptor occurs during its early biosynthesis before cell surface expression (116, 117). This is consistent with a role of this process in targeting receptors to the cell surface, as reported for other GPCRs. Studies on the coexpression of mutant AT₁Rs suggest that this process may have biological significance for the function of cell surface receptors. Also, the coexpression of two mutant AT₁Rs with impaired Ang II binding affinity rescues the ligand binding activity of the native receptor (118). The coexpression of binding (K199A) and G protein coupling-impaired mutant (D125E/R126E/Y127A/M134A) receptors with the wild-type AT₁ receptor has a dominant-negative inhibitory action on its inositol phosphate response, without affecting its agonist-induced ß-arrestin and ERK activation (117). These data are compatible with the hypothesis that AT₁Rs, like rhodopsin, can exist and function as dimers.

Recently, a new mechanism and biological function for AT₁R dimerization has been reported in monocytes, where cross-linking of AT₁R dimers by factor XIIIA transglutaminase appears to promote enhanced signaling and desensitization in vitro and in vivo (119). Elevated levels of cross-linked AT₁Rs were observed in hypertensive patients, and a role of this process in the onset of atherosclerosis was proposed (119). Additional studies are needed to confirm the general relevance of these interesting findings.

The AT₁R also forms heterodimers with the AT₂R, and with the B2 bradykinin and ß-adrenergic receptors (120, 121, 122). Studies on the AT₁R and other GPCRs indicate that, although heterodimerization can occur between several pairs of GPCRs, it is a specific process that involves well-defined partners (115). Heterodimerization of the AT₁ and B2 receptors results in increased activation of G_q and G_i proteins and changes the endocytic pathway of the receptor (120). Although the biological function of this process is not yet known, heterodimerization of these receptors was reported to occur in vivo in platelets and omental vessels and has been proposed to be related to the increased AT₁R responsiveness in preeclampsia (123). Association of the AT₁R with the AT₂R inhibits its signaling activity and function (121), which may contribute to the antagonistic biological effects of the AT₂R on the AT₁R (see above). However, it is not yet known whether the AT₂R has similar inhibitory actions on other GPCRs. This process merits further investigation, because it may explain the previously observed ligand-independent actions of the AT₂R on apoptosis (124). However, it is important to emphasize that not all of the anti-AT₁R effects of the AT₂R are attributable to the heterodimerization of these receptors. The AT₂R can activate phosphotyrosine and serine/threonine phosphatases that inhibit MAPK activation, including MAPK phosphatase 1, protein phosphatase 2A, and SH2 domain-containing phosphatase-1 (10). It also stimulates the formation of bradykinin, NO, and cGMP, which cause vasodilation and exert antiproliferative actions in vessels and attenuate AT₁R-mediated cardiac fibrosis and antinatriuretic effects in the kidney (20).

Recent studies on the physical association of AT₁Rs and ß-adrenergic receptors have clearly demonstrated the potential pharmacological importance of GPCR heterodimerization, because interactions between the two receptors lead to the formation of molecular complexes in which blockade of the AT₁R can inhibit signaling via ß-adrenergic receptors, and vice versa (122). Elucidation of the functional role and biological significance of the heterodimerization of AT₁ with other GPCRs will require further investigation.

	Ang II-STIMULATED ROS GENERATION

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The production of ROS and activation of redox-sensitive signaling pathways mediate many of the actions of Ang II. Under physiological conditions, ROS-dependent redox-signaling processes contribute significantly to the normal cellular responses to Ang II and other humoral mediators. However, excessive accumulation of ROS causes oxidative stress leading to cellular damage or cell death. This is an important factor in the pathophysiological proinflammatory, profibrotic, and mitogenic actions of Ang II and leads to endothelial dysfunction, angiogenesis, vascular and cardiac remodeling during the development of hypertension, atherosclerosis, cardiac and smooth muscle hypertrophy, vasculitis, and diabetes (125).

ROS are produced as intermediates during redox processes that lead to the formation of water from oxygen. The many enzymes that catalyze such reactions include reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, nitric oxide synthases, xanthine oxidases, cytochrome P450s, mitochondrial respiratory chain enzymes, cyclooxygenases, lipoxygenases, and myeloperoxidases. NADPH oxidases are the major source of ROS in leukocytes, but some of the latter enzymes are also important in endothelial cells. The univalent reduction of molecular oxygen by a free electron leads to the formation of highly reactive but unstable superoxide, which only crosses membranes via anion channels. Some of superoxide’s effects result from its rapid reaction with vasodilator and cytoprotective nitric oxide to form highly reactive, toxic peroxinitrate. Superoxide is also converted by dismutases to hydrogen peroxide, which is membrane permeant and has a longer half-life than superoxide. This facilitates the spread of the oxidative signal or stress to other intracellular compartments. Hydrogen peroxide is scavenged by catalase and gluthatione peroxidase but can also be reduced to generate highly active hydroxyl radicals in the presence of metal-containing molecules (e.g. Fe²⁺) (126).

ROS exert their effects by oxidative modification of target molecules, e.g. oxidation of cysteine residues. This is exemplified by the inactivation of protein tyrosine phosphatases by oxidation of conserved cysteines in their active sites, which catalyze the hydrolysis of protein phosphotyrosine residues by forming a cysteinyl-phosphate intermediate (127). This shifts the balance between tyrosine kinases and phosphatases toward phosphorylation, potentiating the effects of Ang II and other humoral mediators that activate tyrosine kinases. ROS also targets numerous other signaling molecules, including ion channels, MAPKs (JNK, p38 MAPK, ERK5), matrix metalloproteinases, and transcription factors [nuclear factor-B (NFB), AP1] (126). In VSMCs, Ang II-induced activation of JNK, p38 MAPK, and ERK5 is ROS-sensitive, whereas ERK1/2 activation is not (125). By these mechanisms, ROS promotes the activation of numerous signaling pathways, some of which further stimulate ROS production and exert positive actions on pathways that amplify signaling. Under physiological conditions, these pathways are controlled by antioxidant mechanisms, but in pathological states such excessive ROS accumulation causes progressive cell damage.

Ang II induces ROS generation in many target tissues, and this appears to result largely from activation of NADPH oxidases. This occurs in VSMCs (128), endothelial cells (129, 130), cardiac cells (131), phagocytic cells (132), and fibroblasts (133). NADPH oxidase was first characterized in neutrophils, where it consists of two membrane-associated (gp91^phox and p22^phox) and four cytosolic (p40^phox, p47^phox, p67^phox and Rac) subunits (126). In phagocytic cells, phosphorylation of p47^phox initiates the assembly of the enzyme complex and causes the respiratory burst by binding to p22^phox. Homologs of gp91^phox (Nox2) are also present in nonphagocytic cells. Nonphagocytic NADPH oxidases include NOX1, NOX3–5, and two related proteins, DUOX1 and DUOX2, which have NADPH oxidase and peroxidase activity. NOX1 is regulated by NOX organizer 1 and NOX activator 1, which are homologous to p47^phoxand p67^phox, suggesting common principles in the assembly of phagocytic and nonphagocytic NADPH oxidases (134). Endothelial cells express NOX1, 2, 4, and 5, whereas VSMCs express NOX1, 4, and 5, and possibly NOX2 (125).

During the rapid and biphasic stimulation of ROS production by Ang II in rat aortic VSMCs, an initial PKC-dependent response during the first minute of agonist stimulation is followed by a slower second increase caused by transactivation of the EGFR (135) (Fig. 4). In accordance with the role of EGFR transactivation during the sustained phase of Ang II-induced ROS generation in VSMCs, inhibition of EGFR transactivation (by AG1478 or Src kinase inhibitors) or of EGFR-mediated ROS production (by inhibitors of Rac or PI 3-kinase) diminishes the sustained increase of ROS generation. Thus, AT₁R-mediated activation of Rac can mediate ROS formation, in addition to its previously reported role in JNK activation (136, 137). Studies by Touyz et al. (138, 139) have also implicated Src kinase and phospholipase D in Ang II-induced ROS generation in VSMCs. However, it is uncertain whether these effects are mediated directly by the AT₁R or result from transactivation of the EGFR or other growth factor receptors. The NADPH oxidase that mediates Ang II-induced ROS formation in VSMCs has yet to be identified.

View larger version (25K): [in this window] [in a new window]   Fig. 4. Potential Mechanisms of Ang II-Induced Activation of NADPH Oxidases and ROS Generation in Phagocytic and Nonphagocytic Cells The NADPH oxidase complex in phagocytic cells, which contains NOX2, is well-established, but elucidation of other components of complexes containing NOX1 and NOX4 may not be complete, as indicated by the question mark (for more details see the text).

Ang II also stimulates the formation of ROS in human neutrophils, leading to activation of MAPKs that may contribute to the pathophysiological effects of the RAS during inflammation (132). Such Ang II-induced ROS formation is mediated by activation of the AT₁R via a PI 3-kinase-dependent pathway, which is also facilitated by ERK1/2 and p38 MAPKs. Ang II also increases cytosolic Ca²⁺ levels and stimulates calcineurin and NFB activities. Although it is clear that Ang II can regulate the function of neutrophils, further studies are required to elucidate the role(s) of AT₁R-mediated second messenger generation in ROS formation and to identify the mechanisms caused by autocrine/paracrine effects of IL-6 and other cytokines released by Ang II.

	Ang II AND CARDIOVASCULAR DISEASE

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Endothelial cell dysfunction is often associated with vascular disorders and is manifested by impaired control of vascular tone, increased adhesiveness of leukocytes, and increased formation of growth factors and cytokines. These processes have been implicated in the development of hypertension, heart failure, atherosclerosis, diabetes, and renal failure. The potential regulatory role of the RAS in endothelial cell function is indicated by the ability of ACE inhibitors to improve endothelial cell parameters in patients with cardiovascular disease and diabetes. This could result from reduced degradation of bradykinin, favoring increased production of nitric oxide and its beneficial effects on the endothelium (54, 145).

Endothelial dysfunction and damage can lead to leukocyte adherence, platelet activation, and vasoconstriction, and ultimately to vascular inflammation, atherosclerosis, and thrombosis. Circulating hormones and other bioactive factors, as well as the biophysical actions of hemodynamic forces, influence the endothelium. Endothelial cells release vasoactive products that affect vasodilatation and vasoconstriction, including nitric oxide (NO), Ang II, and endothelin, both potent vasoconstrictor agents. NO not only modulates vasodilatation and vascular tone but also affects leukocyte adhesion, platelet aggregation, and apoptosis. Clinical evaluation of endothelial function is provided by measurement of brachial artery flow-mediated vasodilatation during reactive hyperemia after a short period of vascular obstruction. Ang II-induced endothelial dysfunction promotes the cytokine-mediated recruitment of monocyte/macrophages into the vascular wall by monocyte chemoattractant protein-1 and vascular cell adhesion and vascular cell adhesion molecule 1. Both ACE inhibitors and AT₁R antagonists have been shown to reduce endothelial dysfunction. The deleterious effects of Ang II are corrected by treatment with PPAR activators, in part by reducing inflammatory responses mediated by NFB and AP1 (146).

Animal studies have shown that the deleterious actions of Ang II in the cardiovascular system can also be caused by treatment with aldosterone and other corticosteroids that activate the mineralocorticoid receptor (MR), particularly at levels inappropriate for the prevailing sodium status. Both hormones have been implicated in the development of endothelial dysfunction, cardiac and vascular inflammation and remodeling, and cardiac arrhythmias. The harmful effects of aldosterone in the heart were discovered in studies on the perivascular and interstitial and ventricular fibrosis associated with arterial hypertension and cardiac failure (147). The finding that Ang II and aldosterone regulate the accumulation of collagen within the rat heart led to the concept that ventricular remodeling in cardiac failure could be treated by aldosterone receptor antagonists (148). This prediction was confirmed by the RALES and EPHESUS trials, in which blockade of the MR by spironolactone and epleronone, respectively, significantly reduced mortality in patients with advanced cardiac failure (149, 150). Aldosterone has also been found to potentiate Ang II-stimulated proliferation of rat VSMCs, possibly by increasing expression of the AT₁R (151, 152). Recent studies on human coronary artery VSMCs have shown that Ang II and aldosterone regulate the transcription of genes involved in vascular fibrosis, inflammation, and calcification (153).

The aldosterone responsible for these adverse cardiovascular actions has been reported to be produced in the heart and to be independent of Ang II, as indicated by its synthesis after myocardial infarction in AT₁R-deficient mice (154, 155). However, in transgenic rats overexpressing human renin and angiotensinogen genes, and treated with dexamethasone and salt, the adrenal is the main source of aldosterone in the heart (156). This is consistent with the observation that angiotensin and salt-induced vascular inflammation in the heart is prevented by adrenalectomy as well as by epleronone (157). These and other findings have demonstrated that aldosterone is a critical factor in the development of Ang II-induced cardiovascular damage (158). Recent studies have shown that activation of the MR can mediate nongenomic actions of its ligands in the heart and blood vessels, and that glucocorticoid occupancy of the MR may also contribute to the development of cardiac inflammatory and fibrotic changes (159, 160).

Ang II also increases the expression of vascular endothelial growth factor (VEGF) and its receptors in aortic wall cells and causes inflammatory changes with monocyte infiltration and vascular remodeling (161). It potentiates VEGF-induced proliferation of endothelial progenitor cells and promotes their VEGF-dependent formation into networks, by increasing the expression of VEGF receptor kinase domain-containing receptors (162) as well as angiopoietin 2 and multiple growth factors (fibroblast growth factor, EGF, platelet-derived growth factor, TGF-ß). AT₁R blockade inhibits angiogenesis and neoplastic cell growth factors in several tumor model systems. Ang II induces VEGF expression in stromal cells of implanted tumors in mice via PKC, AP-1, and NFB, and this appears to be a major determinant of tumor growth and the associated angiogenesis (163). All components of the RAS are expressed in the eye and are abundant in blood vessels and the ganglia cell layer of the developing rat retina (164). Studies in a murine model of ischemic retinopathy showed expression of AT₁R and increased levels of ICAM-I and VEGF, changes that were reduced by treatment with telmisartan, with no effect on physiological neovascularization, by inhibition of the underlying inflammatory changes (165).

	Ang II, ADIPOSE TISSUE, AND METABOLIC REGULATION

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The emergence of obesity as a major metabolic disease, now regarded as a global epidemic, has focused attention on the physiopathology of adipose tissue. Upper body obesity is associated with insulin resistance and endothelial dysfunction, as well as hypertension and increased vasoconstrictor responsiveness to Ang II (166). In addition to hypertension and type 2 diabetes mellitus (DM), the consequences of obesity include dyslipidemia, cardiovascular and liver disease, and arthritis, as well as obstructive sleep apnea and hypoventilation disorder (167). The metabolic syndrome includes obesity, insulin resistance, dyslipidemia, and hypertension, often with hypertriglyceridemia and reduced high-density lipoprotein, as well as hyperuricemia and increased C-reactive protein (168). These features are often associated with endothelial cell dysfunction with impaired control of vascular tone, increased adhesiveness of leukocytes, and increased formation of growth factors and cytokines. These processes have been implicated in the development of hypertension, heart failure, atherosclerosis, diabetes, and renal failure. The potential role of the RAS in endothelial cell dysfunction is indicated by the ability of ACE inhibitors to improve endothelial cell parameters in patients with cardiovascular disease and diabetes (169). This could result in part from reduced degradation of bradykinin, favoring increased production of nitric oxide and its beneficial effects on the endothelium. The efficacy of RAS blockade in reducing the incidence of new-onset diabetes is attributed to hemodynamic actions and decreased insulin resistance, but may also reflect the suppression of an up-regulated RAS within the pancreas in type 2 diabetes (170).

Adipose tissue is now recognized as an active endocrine organ that secretes a variety of hormones, cytokines, and other bioactive proteins. Adipocytes also produce angiotensinogen and other RAS components, including Ang II, and express AT₁R. In addition to Ang II, they produce leptin, adiponectin, TNF, PPAR-, and plasminogen activator inhibitor-1, or PAI-1 (171). Some of these factors act as regulators of insulin secretion and may contribute to the development of insulin resistance. Adiponectin is a potent agent in this regard, and its production is decreased in obesity-related disorders including hypertension, coronary artery disease, the metabolic syndrome, and type 2 DM (172). In adiponectin-deficient mice, pressure overload causes cardiac hypertrophy with increased ERK signaling, whereas increased adiponectin levels exert antihypertrophic actions. Adiponectin also inhibits Ang II-induced apoptosis in human endothelial cells, probably by promoting the association between endothelial nitric oxide synthase and HSP90, and thereby increasing NO production (173).

Further evidence for a role of Ang II in obesity-related disorders was provided by the beneficial effects of AT₁R blockade on insulin sensitivity in adipocytes, with increased production of adiponectin and reduced expression of 11ß-hydroxysteroid dehydrogenase type 1 (174). In hypertensive hypercholesterolemic patients, combined treatment with a statin and an AT₁R antagonist (losartan) improved endothelial function and inflammatory markers more effectively than either agent alone (175). Furthermore, blockade of the RAS increased circulating levels of adiponectin and improved insulin sensitivity in patients with essential hypertension (176). The ability of adiponectin to protect against vascular injury may result from its inhibitory effect on an early step in the development of atherosclerosis, the attachment of monocytes to endothelial cells (177). ACE inhibition has also been found to restore endothelial function by reducing oxidative stress, enhancing insulin resistance, in part by increasing adiponectin levels, and improving cardiac remodeling and renal function (178).

	Ang II AND DIABETES

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The frequent association of DM with hypertension, retinopathy, nephropathy, and cardiovascular disease has implicated the RAS in the initiation and progression of these disorders. This has been demonstrated by clinical trials in which treatment of hypertensive diabetic patients with RAS inhibitors significantly reduced the incidence of vascular complications (170). Such treatment has also been found to reduce the incidence of new-onset type 2 DM by about 30% in subjects with insulin resistance (179). These improvements appear to result from increased perfusion of the microcirculation in skeletal muscle and pancreatic islets, and also from enhanced insulin sensitivity associated with increased leptin and adiponectin production, as well as increased hexokinase activity and glucose transport. Ang II can also cause insulin resistance by interfering with the insulin-stimulated increase in insulin receptor substrate 1-associated PI3K activity (180). The renal RAS is activated in DM, with increased renin and angiotensinogen synthesis, and a rise in tissue angiotensin (181).

Increased activity of the RAS has also been implicated in the development of diabetic cardiomyopathy and diabetic nephropathy, a major cause of end-stage renal disease. The renoprotective action of ACE inhibitors (182) is also conferred by AT₁R blockers, which are recommended for treatment of type 2 DM with macroalbuminuria, nephropathy, or renal insufficiency (183). Because the prevalence of DM is reaching epidemic levels, the potential importance of these agents in the prevention and control of diabetic complications is obvious. The hyperinsulinemia in patients with type 2 diabetes could stimulate Ang II production and proliferation in VSMCs via MAPK signaling and may thereby contribute to the progression of atherosclerosis (184). Blockade of the RAS could thus reduce vascular and tissue Ang II levels and VSMC growth, with beneficial effects on cardiovascular function. In nondiabetic renal disease, combined treatment with ACE inhibition and AT₁R blockade was more effective than either agent alone (185). Interestingly, RAS blockade and receptor antagonists are also effective in reducing glomerular damage and renal chemokine expression in MRL/1pr mice with lupus-like autoimmune renal disease (186).

	Ang II AND CANCER

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In addition to (and perhaps related to) its established proinflammatory actions, there is increasing evidence for an association between the RAS and several types of cancer. Ang II promotes cell growth and neovascularization, and NAD(P)H-derived ROS signaling appears to be an important mediator of Ang II-induced angiogenesis (187). Also, AT₁Rs are expressed in laryngeal (188) and breast cancer (189), and ACE inhibition has been shown to impair the growth of neuroblastoma cells and of pancreatic and renal tumor cells (190, 191, 192). Likewise, AT₁R antagonists have been found to suppress the growth of human pancreatic cancer cells (193) and to reduce tumor growth, angiogenesis, and metastasis of mouse renal cancer cells (194). Similar findings were reported in studies on the growth, angiogenesis, and metastasis of sarcoma, fibrosarcoma, and lung cancer cells in a murine model (195). In addition, Ang II has been shown to stimulate the growth of human breast cancer cells, acting via the AT₁R through a PKC- and EGFR-dependent pathway (196). Furthermore, women with a low-activity genotype of the ACE gene have a 50% lower risk for breast cancer, compared with those with the high activity genotype. Consistent with this, polymorphisms in the AT₁R phenotype are also associated with a reduced incidence of breast cancer (197). A significant role of Ang II in prostate cancer has been indicated by its ability to stimulate the proliferation of prostate cancer cells, which express AT₁R, and that of AT₁R blockers to inhibit cell proliferation and the growth of prostate cancer xenografts (198).

Recent studies in bladder cancer cells revealed that a dominant negative ADAM17 mutant prevented Ang II-induced cleavage of heparin-binding EGF and activation of the EGFR, and inhibited cell proliferation (199). Also, ADAM15 was found to selectively mediate LPA-induced transactivation, indicating that individual ADAMs mediate specific GPCR-induced transactivation of the EGFR. Observations in AT_1A receptor-deficient mice have shown the importance of the host Ang II/AT₁R system in determining tumor-related growth and angiogenesis, by promoting increased macrophage infiltration and fibroblast activity in the tumor stroma, and enhanced production of VEGF (163, 200). The ability of Ang II to stimulate ROS formation may also contribute to its proneoplastic actions, because increased ROS levels induced by other GPCRs in human carcinoma cells have been found to mediate transactivation of the protooncogene MET receptor, which has been implicated in tumor invasion and metastasis (201).

These findings, derived from in vitro studies and animal models, are consistent with the clinical observation that treatment with ACE inhibitors reduced the relative risk of cancer in a retrospective study of hypertensive Scottish patients, in comparison with patients receiving other antihypertensive agents (202). More recently, an ACE polymorphism has been found to be associated with the development of endometrial carcinoma and its onset in younger women (203). These and other studies have emphasized the role of the RAS in neoplasia (204), and the potential therapeutic value of ACE inhibition and AT₁R blockade, perhaps in combination with antiinflammatory agents and specific vaccines, in the treatment of cancer patients (205).

	CONCLUSIONS

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The remarkable array of physiological and pathological actions elicited by Ang II-induced activation of the AT₁R reflects its extraordinarily diverse repertoire of signaling mechanisms and pathways, including some that require stringent counterregulatory control systems to prevent excessive activity leading to deleterious cellular growth and proliferation. This is indicative of the scope and biological significance of angiotensin’s numerous actions, and the roles of critical signaling mechanisms that are susceptible to dysfunction leading to progressive inflammatory and degenerative conditions that underlie major disease entities. On the other hand, the availability of highly effective agents for inhibition of Ang II formation, and selective blockade of the AT₁R, have led to the identification of many of the hitherto unrecognized pathological actions of Ang II. The application of therapeutic approaches based on this recently acquired knowledge is facilitating the amelioration or abolition of many of the deleterious effects of inappropriately activated Ang II/AT₁R signaling pathways, which are now known to contribute to several disease states. In addition to hypertension per se, these include an impressive spectrum of disorders ranging from endothelial dysfunction and atheroma to cardiac hypertrophy, atrial fibrillation, cardiac failure, renal disease, obesity and the metabolic syndrome, DM and insulin resistance, and cancer. These revelations are in marked contrast to the attitudes of only two decades ago, when there was still debate about the physiological actions of Ang II, and little or no insight into its role in disease states.

New signaling mechanisms, including G protein-dependent and -independent effects of AT₁R activation, are emerging that begin to explain the unexpectedly broad clinical significance of the RAS. It is generally accepted that blockade of the local generation of Ang II is a key factor in the clinical benefits of ACE inhibition and AT₁R antagonists. Ang II can activate cytokine signaling pathways in cardiovascular cells and is emerging as a typical cytokine that can regulate immune cells and inflammatory processes. However, the exact signal transduction mechanism of Ang II in leukocytes and macrophages, and the biological roles of AT₁R dimerization and G protein-independent signaling pathways, need additional investigation and further elucidation.

It is now well established that the clinical benefits of ACE inhibition and AT₁R blockers extend far beyond their control of blood pressure, and include the reduction of mortality from myocardial infarction, heart failure, atherosclerosis, stroke, diabetes, peripheral vascular disease, chronic renal disease, and stroke. Some of these effects are attributable to inhibition of aldosterone secretion, which in addition to its actions on sodium retention and blood pressure, is a significant risk factor for cardiac fibrosis and heart failure (158). However, the main advantages of ACE inhibitors stem from their ability to reduce Ang II-induced damage to the cardiovascular and renal systems, and to retard the progress of DM. Current speculations about the pervasive role of the RAS and Ang II in many age-related diseases have yet to be confirmed. However, there is already abundant evidence for the ability of ACE inhibition and AT₁R blockade to extend the life and well-being of patients with renal disease, heart failure, diabetes, and possibly cancer, major illnesses that are responsible for considerable suffering and mortality, and account for much of the increasing expenditure on medical treatment and other aspects of health care. It is possible that other, previously unrecognized, consequences of disordered RAS function have yet to be discovered.

	FOOTNOTES

 
This work was supported by in part by a Collaborative Research Initiative Grant from the Wellcome Trust (069416/Z/02/Z) and by grants from the Hungarian Ministry of Public Health (ETT 036/2003) and the Hungarian Science Foundation (OTKA T-046445) (to L.H.).

L.H. and K.J.C. have nothing to declare.

First Published Online September 1, 2005

Abbreviations: ACE, Angiotensin-converting enzyme; Ang II, angiotensin II; AP, activator protein; ARAP-1, Ang II receptor-associated protein 1; ATRAP, AT₁ receptor-associated protein; AT₁R, AT₁ receptor; DM, diabetes mellitus; EGF, epidermal growth factor; EGFR, EGF receptor; GIT1, GPCR kinase-interacting protein 1; GLP, GDP/GTP exchange factor-like protein; GPCR, G protein-coupled receptor; HEK, human embryonic kidney; Jak, Janus kinase; JNK, c-Jun NH₂-terminal kinase; MCP-1, monocyte chemoattractant protein-1; MR, mineralocorticoid receptor; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLC, phospholipase C; RAS, renin-angiotensin system; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.

Received for publication December 27, 2004. Accepted for publication August 24, 2005.

	REFERENCES

TOP ABSTRACT INTRODUCTION THE RENIN-ANGIOTENSIN SYSTEM BIOLOGICAL ROLES OF LOCAL... CLASSICAL G PROTEIN-MEDIATED... G PROTEIN-INDEPENDENT EFFECTS OF... MODULATION OF AT1R FUNCTION... Ang II-STIMULATED ROS GENERATION Ang II AND CARDIOVASCULAR... Ang II, ADIPOSE TISSUE,... Ang II AND DIABETES Ang II AND CANCER CONCLUSIONS REFERENCES

 

1. Tigerstedt R, Bergman PG 1898 Niere and Kresilauf. Scand Arch Physiol 8:223–271
2. Braun-Menendez E, Fasciolo JC, Leloir LF, Muoz JM 1940 The substance causing renal hypertension. J Physiol (Lond) 98:283–298[Free Full Text]
3. Page IH, Helmer OM 1940 A crystalline pressor substance (angiotonin) resulting from the reaction between renin and renin activator. J Exp Med 71:29–42[Abstract]
4. Glossmann H, Baukal A, Catt KJ 1974 Angiotensin II receptors in bovine adrenal cortex. Modification of angiotensin II binding by guanyl nucleotides. J Biol Chem 249:664–666[Abstract/Free Full Text]
5. De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T 2000 International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472[Abstract/Free Full Text]
6. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE 1991 Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature 351:233–236[CrossRef][Medline]
7. Sasaki K, Yamano Y, Bardhan S, Iwai N, Murray JJ, Hasegawa M, Matsuda Y, Inagami T 1991 Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor. Nature 351:230–233[CrossRef][Medline]
8. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T 1993 Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem 268:24543–24546[Abstract/Free Full Text]
9. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ 1993 Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem 268:24539–24542[Abstract/Free Full Text]
10. Nouet S, Nahmias C 2000 Signal transduction from the angiotensin II AT₂ receptor. Trends Endocrinol Metab 11:1–6[CrossRef][Medline]
11. Sequeira Lopez ML, Gomez RA 2004 The role of angiotensin II in kidney embryogenesis and kidney abnormalities. Curr Opin Nephrol Hypertens 13:117–122[Medline]
12. Crowley SD, Tharaux PL, Audoly LP, Coffman TM 2004 Exploring type I angiotensin (AT1) receptor functions through gene targeting. Acta Physiol Scand 181:561–570[CrossRef][Medline]
13. Lavoie JL, Sigmund CD 2003 Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology 144:2179–2183[Abstract/Free Full Text]
14. Ferrario C, Abdelhamed AI, Moore M 2004 AII antagonists in hypertension, heart failure, and diabetic nephropathy: focus on losartan. Curr Med Res Opin 20:279–293[CrossRef][Medline]
15. Re RN 2003 Intracellular renin and the nature of intracrine enzymes. Hypertension 42:117–122[Abstract/Free Full Text]
16. Baker KM, Chernin MI, Schreiber T, Sanghi S, Haiderzaidi S, Booz GW, Dostal DE, Kumar R 2004 Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy. Regul Pept 120:5–13[CrossRef][Medline]
17. Danser AH 2003 Local renin-angiotensin systems: the unanswered questions. Int J Biochem Cell Biol 35:759–768[CrossRef][Medline]
18. Zou Y, Akazawa H, Qin Y, Sano M, Takano H, Minamino T, Makita N, Iwanaga K, Zhu W, Kudoh S, Toko H, Tamura K, Kihara M, Nagai T, Fukamizu A, Umemura S, Iiri T, Fujita T, Komuro I 2004 Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat Cell Biol 6:499–506[CrossRef][Medline]
19. Hunyady L, Turu G 2004 The role of the AT(1) angiotensin receptor in cardiac hypertrophy: angiotensin II receptor or stretch sensor? Trends Endocrinol Metab 15:405–408[CrossRef][Medline]
20. Carey RM, Siragy HM 2003 Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 24:261–271[Abstract/Free Full Text]
21. Thomas WG, Mendelsohn FA 2003 Angiotensin receptors: form and function and distribution. Int J Biochem Cell Biol 35:774–779[CrossRef][Medline]
22. Ferrario CM, Chappell MC 2004 Novel angiotensin peptides. Cell Mol Life Sci 61:2720–2727[CrossRef][Medline]
23. Schelleman H, Stricker BH, De Boer A, Kroon AA, Verschuren MW, Van Duijn CM, Psaty BM, Klungel OH 2004 Drug-gene interactions between genetic polymorphisms and antihypertensive therapy. Drugs 64:1801–1816[CrossRef][Medline]
24. Schurmann M, Reichel P, Muller-Myhsok B, Dieringer T, Wurm K, Schlaak M, Muller-Quernheim J, Schwinger E 2001 Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis. J Intern Med 249:77–83[CrossRef][Medline]
25. Fei DT, Coghlan JP, Fernley RT, Scoggins BA, Tregear GW 1980 Peripheral production of angiotensin II and III in sheep. Circ Res 46:I135–I137
26. Spät A, Hunyady L 2004 Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev 84:489–539[Abstract/Free Full Text]
27. Sernia C 2001 A critical appraisal of the intrinsic pancreatic angiotensin-generating system. JOP 2:50–55[Medline]
28. Nielsen AH, Schauser KH, Poulsen K 2000 Current topic: the uteroplacental renin-angiotensin system. Placenta 21:468–477[CrossRef][Medline]
29. Albiston AL, McDowall SG, Matsacos D, Sim P, Clune E, Mustafa T, Lee J, Mendelsohn FA, Simpson RJ, Connolly LM, Chai SY 2001 Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem 276:48623–48626[Abstract/Free Full Text]
30. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins TA, Albiston AL 2004 The angiotensin IV/AT4 receptor. Cell Mol Life Sci 61:2728–2737[CrossRef][Medline]
31. Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T 2003 Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 100:8258–8263[Abstract/Free Full Text]
32. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G 2000 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145–153[Abstract/Free Full Text]
33. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H 2002 Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003[CrossRef][Medline]
34. Brunner HR, Gavras H, Waeber B, Kershaw GR, Turini GA, Vukovich RA, McKinstry DN, Gavras I 1979 Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med 90:19–23[Abstract/Free Full Text]
35. Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlof B, Deanfield J, Diez J, Drexler H, Ferrari R, van Gilst W, Hansson L, Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Luscher T, Mancini J, Mimran A, Pepine C, Rabelink T, Remme W, Ruilope L, Ruzicka M, Schunkert H, Swedberg K, Unger T, Vaughan D, Weber M 2001 The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. Am J Cardiol 88:1L–20L[Medline]
36. Keys JR, Greene EA, Koch WJ, Eckhart AD 2002 Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature. Hypertension 40:660–666[Abstract/Free Full Text]
37. Hescheler J, Rosenthal W, Hinsch K-D, Wulfern M, Trautwein W, Schultz G 1988 Angiotensin II-induced stimulation of voltage-dependent Ca2+ currents in an adrenal cortical cell line. EMBO J 7:619–624[Medline]
38. Lu HK, Fern RJ, Luthin D, Linden J, Liu LP, Cohen CJ, Barrett PQ 1996 Angiotensin II stimulates T-type Ca²⁺ channel currents via activation of a G protein, G_i. Am J Physiol Cell Physiol 271:C1340–C1349
39. Maturana AD, Casal AJ, Demaurex N, Vallotton MB, Capponi AM, Rossier MF 1999 Angiotensin II negatively modulates L-type calcium channels through a pertussis toxin-sensitive G protein in adrenal glomerulosa cells. J Biol Chem 274:19943–19948[Abstract/Free Full Text]
40. Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW 1998 Temporal dispersion of activation of phospholipase C-ß1 and - isoforms by angiotensin II in vascular smooth muscle cells. Role of q/11, 12, and ß G protein subunits. J Biol Chem 273:19772–19777[Abstract/Free Full Text]
41. Macrez N, Morel JL, Kalkbrenner F, Viard P, Schultz G, Mironneau J 1997 A ß dimer derived from G₁₃ transduces the angiotensin AT₁ receptor signal to stimulation of Ca²⁺ channels in rat portal vein myocytes. J Biol Chem 272:23180–23185[Abstract/Free Full Text]
42. Ushio-Fukai M, Alexander RW, Akers M, Lyons PR, Lassegue B, Griendling KK 1999 Angiotensin II receptor coupling to phospholipase D is mediated by the ß subunits of heterotrimeric G proteins in vascular smooth muscle cells. Mol Pharmacol 55:142–149[Abstract/Free Full Text]
43. Rattan S, Puri RN, Fan YP 2003 Involvement of rho and rho-associated kinase in sphincteric smooth muscle contraction by angiotensin II. Exp Biol Med (Maywood) 228:972–981[Abstract/Free Full Text]
44. Baukal AJ, Hunyady L, Catt KJ, Balla T 1994 Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. J Biol Chem 269:24546–24549[Abstract/Free Full Text]
45. Saito Y, Berk BC 2002 Angiotensin II-mediated signal transduction pathways. Curr Hypertens Rep 4:167–171[Medline]
46. Yin G, Yan C, Berk BC 2003 Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35:780–783[CrossRef][Medline]
47. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R 1997 Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase . Science 275:394–397[Abstract/Free Full Text]
48. Luchtefeld M, Drexler H, Schieffer B 2001 Role of G ß-subunit in angiotensin II-type 1 receptor signaling. Biochem Biophys Res Commun 280:756–760[CrossRef][Medline]
49. Ali MS, Sayeski PP, Dirksen LB, Hayzer DJ, Marrero MB, Bernstein KE 1997 Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT₁ receptor. J Biol Chem 272:23382–23388[Abstract/Free Full Text]
50. Kyaw M, Yoshizumi M, Tsuchiya K, Kagami S, Izawa Y, Fujita Y, Ali N, Kanematsu Y, Toida K, Ishimura K, Tamaki T 2004 Src and Cas are essentially but differentially involved in angiotensin II-stimulated migration of vascular smooth muscle cells via extracellular signal-regulated kinase 1/2 and c-Jun NH2-terminal kinase activation. Mol Pharmacol 65:832–841[Abstract/Free Full Text]
51. Haendeler J, Yin G, Hojo Y, Saito Y, Melaragno M, Yan C, Sharma VK, Heller M, Aebersold R, Berk BC 2003 GIT1 mediates Src-dependent activation of phospholipase C by angiotensin II and epidermal growth factor. J Biol Chem 278:49936–49944[Abstract/Free Full Text]
52. Yin G, Haendeler J, Yan C, Berk BC 2004 GIT1 functions as a scaffold for MEK1-extracellular signal-regulated kinase 1 and 2 activation by angiotensin II and epidermal growth factor. Mol Cell Biol 24:875–885[Abstract/Free Full Text]
53. Yin G, Zheng Q, Yan C, Berk BC 2005 GIT1 is a scaffold for ERK1/2 activation in focal adhesions. J Biol Chem 280:27705–27712[Abstract/Free Full Text]
54. Schiffrin EL, Touyz RM 2004 From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol 287:H435–H446
55. Wang Z, Rao PJ, Shillcutt SD, Newman WH 2005 Angiotensin II induces proliferation of human cerebral artery smooth muscle cells through a basic fibroblast growth factor (bFGF) dependent mechanism. Neurosci Lett 373:38–41[CrossRef][Medline]
56. Zhang A, Ding G, Huang S, Wu Y, Pan X, Guan X, Chen R, Yang T 2005 c-Jun NH2-terminal kinase mediation of angiotensin II-induced proliferation of human mesangial cells. Am J Physiol Renal Physiol 288:F1118–F1124
57. Chiu T, Santiskulvong C, Rozengurt E 2005 EGF receptor transactivation mediates ANG II-stimulated mitogenesis in intestinal epithelial cells through the PI3-kinase/Akt/mTOR/p70S6K1 signaling pathway. Am J Physiol Gastrointest Liver Physiol 288:G182–G194
58. Foster RH 2004 Reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in adrenal glomerulosa cells. J Mol Endocrinol 32:893–902[Abstract]
59. Otis M, Campbell S, Payet MD, Gallo-Payet N 2005 Angiotensin II stimulates protein synthesis and inhibits proliferation in primary cultures of rat adrenal glomerulosa cells. Endocrinology 146:633–642[Abstract/Free Full Text]
60. Rossi F, Ferraresi A, Romagni P, Silvestroni L, Santiemma V 2002 Angiotensin II stimulates contraction and growth of testicular peritubular myoid cells in vitro. Endocrinology 143:3096–3104[Abstract/Free Full Text]
61. Takeda H, Katagata Y, Hozumi Y, Kondo S 2004 Effects of angiotensin II receptor signaling during skin wound healing. Am J Pathol 165:1653–1662[Abstract/Free Full Text]
62. Melaragno MG, Wuthrich DA, Poppa V, Gill D, Lindner V, Berk BC, Corson MA 1998 Increased expression of Axl tyrosine kinase after vascular injury and regulation by G protein-coupled receptor agonists in rats. Circ Res 83:697–704[Abstract/Free Full Text]
63. Heeneman S, Haendeler J, Saito Y, Ishida M, Berk BC 2000 Angiotensin II induces transactivation of two different populations of the platelet-derived growth factor ß receptor. Key role for the p66 adaptor protein Shc. J Biol Chem 275:15926–15932[Abstract/Free Full Text]
64. Du J, Sperling LS, Marrero MB, Phillips L, Delafontaine P 1996 G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin- and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor. Biochem Biophys Res Commun 218:934–939[CrossRef][Medline]
65. Shah BH, Yesilkaya A, Olivares-Reyes JA, Chen HD, Hunyady L, Catt KJ 2004 Differential pathways of angiotensin II-induced extracellularly regulated kinase 1/2 phosphorylation in specific cell types: role of heparin-binding epidermal growth factor. Mol Endocrinol 18:2035–2048[Abstract/Free Full Text]
66. Eguchi S, Dempsey PJ, Frank GD, Motley ED, Inagami T 2001 Activation of MAPKs by angiotensin II in vascular smooth muscle cells. Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK. J Biol Chem 276:7957–7962[Abstract/Free Full Text]
67. Frank GD, Eguchi S 2003 Activation of tyrosine kinases by reactive oxygen species in vascular smooth muscle cells: significance and involvement of EGF receptor transactivation by angiotensin II. Antioxid Redox Signal 5:771–780[CrossRef][Medline]
68. Shah BH, Catt KJ 2003 A central role of EGF receptor transactivation in angiotensin II -induced cardiac hypertrophy. Trends Pharmacol Sci 24:239–244[Medline]
69. Garcia-Sainz JA, Garcia-Caballero A, Gonzalez-Espinosa C 1998 Angiotensin AT1 receptors in clone 9 rat liver cells: Ca2+ signaling and c-fos expression. Eur J Pharmacol 362:235–243[CrossRef][Medline]
70. Shah BH, Catt KJ 2002 Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase C, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Mol Pharmacol 61:343–351[Abstract/Free Full Text]
71. Olivares-Reyes JA, Shah BH, Hernandez-Aranda J, Garcia-Caballero A, Farshori MP, Garcia-Sainz JA, Catt KJ 2005 Agonist-induced interactions between angiotensin AT1 and epidermal growth factor receptors. Mol Pharmacol 68:356–364[Abstract/Free Full Text]
72. Touyz RM, Schiffrin EL 2000 Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 52:639–672[Abstract/Free Full Text]
73. Claing A, Laporte SA, Caron MG, Lefkowitz RJ 2002 Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and ss-arrestin proteins. Prog Neurobiol 66:61–79[CrossRef][Medline]
74. Luttrell LM, Lefkowitz RJ 2002 The role of ß-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 115:455–465[Abstract/Free Full Text]
75. Gaborik Z, Hunyady L 2004 Intracellular trafficking of hormone receptors. Trends Endocrinol Metab 15:286–293[CrossRef][Medline]
76. Prossnitz ER 2004 Novel roles for arrestins in the post-endocytic trafficking of G protein-coupled receptors. Life Sci 75:893–899[CrossRef][Medline]
77. Thomas WG, Qian H 2003 Arresting angiotensin type 1 receptors. Trends Endocrinol Metab 14:130–136[CrossRef][Medline]
78. Hunyady L, Bor M, Balla T, Catt KJ 1994 Identification of a cytoplasmic Ser-Thr-Leu motif that determines agonist-induced internalization of the AT₁ angiotensin receptor. J Biol Chem 269:31378–31382[Abstract/Free Full Text]
79. Smith RD, Hunyady L, Olivares-Reyes JA, Mihalik B, Jayadev S, Catt KJ 1998 Agonist-induced phosphorylation of the angiotensin AT_1a receptor is localized to a serine/threonine-rich region of its cytoplasmic tail. Mol Pharmacol 54:935–941[Abstract/Free Full Text]
80. Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS 2000 Differential affinities of visual arrestin, ß arrestin1, and ß arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 275:17201–17210[Abstract/Free Full Text]
81. Oakley RH, Laporte SA, Holt JA, Barak LS, Caron MG 2001 Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-ß-arrestin complexes after receptor endocytosis. J Biol Chem 276:19452–19460[Abstract/Free Full Text]
82. Wei H, Ahn S, Shenoy SK, Karnik SS, Hunyady L, Luttrell LM, Lefkowitz RJ 2003 Independent ß-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci USA 100:10782–10787[Abstract/Free Full Text]
83. DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW 2000 ß-Arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148:1267–1281[Abstract/Free Full Text]
84. Ge L, Ly Y, Hollenberg M, Defea K 2003 A ß-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis. J Biol Chem 278:34418–34426[Abstract/Free Full Text]
85. Ge L, Shenoy SK, Lefkowitz RJ, Defea K 2004 Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both ß-arrestin-1 and -2. J Biol Chem 279:55419–55424[Abstract/Free Full Text]
86. Hunton DL, Barnes WG, Kim J, Ren XR, Violin JD, Reiter E, Milligan G, Patel DD, Lefkowitz RJ 2005 ß-Arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis. Mol Pharmacol 67:1229–1236[Abstract/Free Full Text]
87. Seta K, Nanamori M, Modrall JG, Neubig RR, Sadoshima J 2002 AT1 receptor mutant lacking heterotrimeric G protein coupling activates the Src-Ras-ERK pathway without nuclear translocation of ERKs. J Biol Chem 277:9268–9277[Abstract/Free Full Text]
88. Miura S, Zhang J, Matsuo Y, Saku K, Karnik SS 2004 Activation of extracellular signal-activated kinase by angiotensin II-induced Gq-independent epidermal growth factor receptor transactivation. Hypertens Res 27:765–770[CrossRef][Medline]
89. Luttrell LM, Ferguson SSG, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ 1999 ß-Arrestin-dependent formation of ß2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661[Abstract/Free Full Text]
90. Hunyady L, Zhang M, Jagadeesh G, Bor M, Balla T, Catt KJ 1996 Dependence of agonist activation on a conserved apolar residue in the third intracellular loop of the AT₁ angiotensin receptor. Proc Natl Acad Sci USA 93:10040–10045[Abstract/Free Full Text]
91. Haendeler J, Ishida M, Hunyady L, Berk BC 2000 The third cytoplasmic loop of the angiotensin II type 1 receptor exerts differential effects on extracellular signal-regulated kinase (ERK1/ERK2) and apoptosis via Ras- and Rap1-dependent pathways. Circ Res 86:729–736[Abstract/Free Full Text]
92. Booz GW, Day JN, Baker KM 2002 Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure. J Mol Cell Cardiol 34:1443–1453[CrossRef][Medline]
93. Phillips MI, Kagiyama S 2002 Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs 3:569–577[Medline]
94. Chen X, Wang J, Zhou F, Wang X, Feng Z 2003 STAT proteins mediate angiotensin II-induced production of TIMP-1 in human proximal tubular epithelial cells. Kidney Int 64:459–467[CrossRef][Medline]
95. Mascareno E, Siddiqui MA 2000 The role of Jak/STAT signaling in heart tissue renin-angiotensin system. Mol Cell Biochem 212:171–175[CrossRef][Medline]
96. Wang TL, Yang YH, Chang H, Hung CR 2004 Angiotensin II signals mechanical stretch-induced cardiac matrix metalloproteinase expression via JAK-STAT pathway. J Mol Cell Cardiol 37:785–794[CrossRef][Medline]
97. Ihle JN 1996 STATs: signal transducers and activators of transcription. Cell 84:331–334[CrossRef][Medline]
98. Bhat GJ, Thekkumkara TJ, Thomas WG, Conrad KM, Baker KM 1994 Angiotensin II stimulates sis-inducing factor-like DNA binding activity. Evidence that the AT_1A receptor activates transcription factor-Stat91 and/or a related protein. J Biol Chem 269:31443–31449[Abstract/Free Full Text]
99. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE 1995 Direct stimulation of Jak/STAT pathway by the angiotensin II AT₁ receptor. Nature 375:247–250[CrossRef][Medline]
100. Venema RC, Ju H, Venema VJ, Schieffer B, Harp JB, Ling BN, Eaton DC, Marrero MB 1998 Angiotensin II-induced association of phospholipase C1 with the G-protein-coupled AT₁ receptor. J Biol Chem 273:7703–7708[Abstract/Free Full Text]
101. Seta K, Sadoshima J 2003 Phosphorylation of tyrosine 319 of the angiotensin II type 1 receptor mediates angiotensin II-induced trans-activation of the epidermal growth factor receptor. J Biol Chem 278:9019–9026[Abstract/Free Full Text]
102. Inada Y, Nakane T, Chiba S 2003 Relationship between ligand binding and YIPP motif in the C-terminal region of human AT1 receptor. Biochim Biophys Acta 1640:33–41[Medline]
103. Frank GD, Saito S, Motley ED, Sasaki T, Ohba M, Kuroki T, Inagami T, Eguchi S 2002 Requirement of Ca(2+) and PKCdelta for Janus kinase 2 activation by angiotensin II: involvement of PYK2. Mol Endocrinol 16:367–377[Abstract/Free Full Text]
104. Doan TN, Ali MS, Bernstein KE 2001 Tyrosine kinase activation by the angiotensin II receptor in the absence of calcium signaling. J Biol Chem 276:20954–20958[Abstract/Free Full Text]
105. Daviet L, Lehtonen JY, Tamura K, Griese DP, Horiuchi M, Dzau VJ 1999 Cloning and characterization of ATRAP, a novel protein that interacts with the angiotensin II type 1 receptor. J Biol Chem 274:17058–17062[Abstract/Free Full Text]
106. Guo DF, Chenier I, Tardif V, Orlov SN, Inagami T 2003 Type 1 angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane. Biochem Biophys Res Commun 310:1254–1265[CrossRef][Medline]
107. Shivakumar BR, Wang Z, Hammond TG, Harris RC 2004 EP24.15 interacts with the angiotensin II type I receptor and bradykinin B(2) receptor. Cell Biochem Funct 23:195–204[CrossRef]
108. Guo DF, Tardif V, Ghelima K, Chan JS, Ingelfinger JR, Chen X, Chenier I 2004 A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells. J Biol Chem 279:21109–21120[Abstract/Free Full Text]
109. Lopez-Ilasaca M, Liu X, Tamura K, Dzau VJ 2003 The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin II signaling. Mol Biol Cell 14:5038–5050[Abstract/Free Full Text]
110. Tanaka Y, Tamura K, Koide Y, Sakai M, Tsurumi Y, Noda Y, Umemura M, Ishigami T, Uchino K, Kimura K, Horiuchi M, Umemura S 2005 The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy. FEBS Lett 579:1579–1586[CrossRef][Medline]
111. Ishizaka N, Griendling KK, Lassegue B, Alexander RW 1998 Angiotensin II type 1 receptor: relationship with caveolae and caveolin after initial agonist stimulation. Hypertension 32:459–466[Abstract/Free Full Text]
112. Leclerc PC, Auger-Messier M, Lanctot PM, Escher E, Leduc R, Guillemette G 2002 A polyaromatic caveolin-binding-like motif in the cytoplasmic tail of the type 1 receptor for angiotensin II plays an important role in receptor trafficking and signaling. Endocrinology 143:4702–4710[Abstract/Free Full Text]
113. Zuo L, Ushio-Fukai M, Ikeda S, Hilenski L, Patrushev N, Alexander RW 2005 Caveolin-1 is essential for activation of Rac1 and NAD(P)H oxidase after angiotensin II type 1 receptor stimulation in vascular smooth muscle cells. Role in redox signaling and vascular hypertrophy. Arterioscler Thromb Vasc Biol 25:1824–1830[Abstract/Free Full Text]
114. Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A 2003 Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem 278:21655–21662[Abstract/Free Full Text]
115. Milligan G 2004 G protein-coupled receptor dimerization: function and ligand pharmacology. Mol Pharmacol 66:1–7[Abstract/Free Full Text]
116. Jensen AA, Hansen JL, Sheikh SP, Brauner-Osborne H 2002 Probing intermolecular protein-protein interactions in the calcium-sensing receptor homodimer using bioluminescence resonance energy transfer (BRET). Eur J Biochem 269:5076–5087[Medline]
117. Hansen JL, Theilade J, Haunso S, Sheikh SP 2004 Oligomerization of wild type and nonfunctional mutant angiotensin II type I receptors inhibits gq protein signaling but not ERK activation. J Biol Chem 279:24108–24115[Abstract/Free Full Text]
118. Monnot C, Bihoreau C, Conchon S, Curnow KM, Corvol P, Clauser E 1996 Polar residues in the transmembrane domains of the type 1 angiotensin II receptor are required for binding and coupling: reconstitution of the binding site by co-expression of two deficient mutants. J Biol Chem 271:1507–1513[Abstract/Free Full Text]
119. AbdAlla S, Lother H, Langer A, el Faramawy Y, Quitterer U 2004 Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis. Cell 119:343–354[CrossRef][Medline]
120. AbdAlla S, Lother H, Quitterer U 2000 AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407:94–98[CrossRef][Medline]
121. AbdAlla S, Lother H, Abdel-tawab AM, Quitterer U 2001 The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem 276:39721–39726[Abstract/Free Full Text]
122. Barki-Harrington L, Luttrell LM, Rockman HA 2003 Dual inhibition of ß-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo. Circulation 108:1611–1618[Abstract/Free Full Text]
123. AbdAlla S, Lother H, el Massiery A, Quitterer U 2001 Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med 7:1003–1009[CrossRef][Medline]
124. Miura S, Karnik SS 2000 Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. EMBO J 19:4026–4035[CrossRef][Medline]
125. Cai H, Griendling KK, Harrison DG 2003 The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 24:471–478[CrossRef][Medline]
126. Droge W 2002 Free radicals in the physiological control of cell function. Physiol Rev 82:47–95[Abstract/Free Full Text]
127. Denu JM, Tanner KG 1998 Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37:5633–5642[CrossRef][Medline]
128. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW 1994 Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74:1141–1148[Abstract/Free Full Text]
129. Ushio-Fukai M, Tang Y, Fukai T, Dikalov SI, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW 2002 Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 91:1160–1167[Abstract/Free Full Text]
130. Zhang H, Schmeisser A, Garlichs CD, Plotze K, Damme U, Mugge A, Daniel WG 1999 Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res 44:215–222[Abstract/Free Full Text]
131. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM 2002 Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105:293–296[Abstract/Free Full Text]
132. El Bekay R, Alvarez M, Monteseirin J, Alba G, Chacon P, Vega A, Martin-Nieto J, Jimenez J, Pintado E, Bedoya FJ, Sobrino F 2003 Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-B. Blood 102:662–671[Abstract/Free Full Text]
133. Rey FE, Pagano PJ 2002 The reactive adventitia: fibroblast oxidase in vascular function. Arterioscler Thromb Vasc Biol 22:1962–1971[Abstract/Free Full Text]
134. Geiszt M, Leto TL 2004 The Nox family of NAD(P)H oxidases: host defense and beyond. J Biol Chem 279:51715–51718[Free Full Text]
135. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK 2002 Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res 91:406–413[Abstract/Free Full Text]
136. Murasawa S, Matsubara H, Mori Y, Masaki H, Tsutsumi Y, Shibasaki Y, Kitabayashi I, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Iba S, Iwasaka T 2000 Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase. J Biol Chem 275:26856–26863[Abstract/Free Full Text]
137. Huszár T, Mucsi I, Antus B, Terebessy T, Jeney C, Masszi A, Hunyady L, Mihalik B, Goldberg HJ, Thekkumkara TJ, Rosivall L 2001 Extracellular signal-regulated kinase and the small GTP-binding protein p21Rac1 are involved in the regulation of gene transcription by angiotensin II. Exp Nephrol 9:142–149[CrossRef][Medline]
138. Touyz RM, Schiffrin EL 1999 Ang II-stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension 34:976–982[Abstract/Free Full Text]
139. Touyz RM, Yao G, Schiffrin EL 2003 c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 23:981–987[Abstract/Free Full Text]
140. Lavigne MC, Malech HL, Holland SM, Leto TL 2001 Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation 104:79–84[Abstract/Free Full Text]
141. Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG 2002 Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40:511–515[Abstract/Free Full Text]
142. Barry-Lane PA, Patterson C, van der MM, Hu Z, Holland SM, Yeh ET, Runge MS 2001 p47phox is required for atherosclerotic lesion progression in ApoE(–/–) mice. J Clin Invest 108:1513–1522[CrossRef][Medline]
143. Kirk EA, Dinauer MC, Rosen H, Chait A, Heinecke JW, LeBoeuf RC 2000 Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. Arterioscler Thromb Vasc Biol 20:1529–1535[Abstract/Free Full Text]
144. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK 2004 Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 24:677–683[Abstract/Free Full Text]
145. Endemann DH, Schiffrin EL 2004 Endothelial dysfunction. J Am Soc Nephrol 15:1983–1992[Abstract/Free Full Text]
146. Schiffrin EL 2005 Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol 288:H1037–H1043
147. Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT 1990 Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 67:1355–1364[Abstract/Free Full Text]
148. Weber KT, Brilla CG, Campbell SE 1992 Regulatory mechanisms of myocardial hypertrophy and fibrosis: results of in vivo studies. Cardiology 81:266–273[Medline]
149. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J 1999 The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717[Abstract/Free Full Text]
150. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M 2003 Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321[Abstract/Free Full Text]
151. Ullian ME, Hutchison FN, Hazen-Martin DJ, Morinelli TA 1993 Angiotensin II-aldosterone interactions on protein synthesis in vascular smooth muscle cells. Am J Physiol 264:C1525–C1531
152. Xiao F, Puddefoot JR, Barker S, Vinson GP 2004 Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension 44:340–345[Abstract/Free Full Text]
153. Jaffe IZ, Mendelsohn ME 2005 Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 96:643–650[Abstract/Free Full Text]
154. Silvestre JS, Robert V, Heymes C, Aupetit-Faisant B, Mouas C, Moalic JM, Swynghedauw B, Delcayre C 1998 Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J Biol Chem 273:4883–4891[Abstract/Free Full Text]
155. Katada J, Meguro T, Saito H, Ohashi A, Anzai T, Ogawa S, Yoshikawa T 2005 Persistent cardiac aldosterone synthesis in angiotensin II type 1A receptor-knockout mice after myocardial infarction. Circulation 111:2157–2164[Abstract/Free Full Text]
156. Fiebeler A, Nussberger J, Shagdarsuren E, Rong S, Hilfenhaus G, Al Saadi N, Dechend R, Wellner M, Meiners S, Maser-Gluth C, Jeng AY, Webb RL, Luft FC, Muller DN 2005 Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation 111:3087–3094[Abstract/Free Full Text]
157. Rocha R, Martin-Berger CL, Yang P, Scherrer R, Delyani J, McMahon E 2002 Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology 143:4828–4836[Abstract/Free Full Text]
158. Struthers AD, MacDonald TM 2004 Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res 61:663–670[Abstract/Free Full Text]
159. Michea L, Delpiano AM, Hitschfeld C, Lobos L, Lavandero S, Marusic ET 2005 Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels. Endocrinology 146:973–980[Abstract/Free Full Text]
160. Mihailidou AS, Funder JW 2005 Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system. Steroids 70:347–351[CrossRef][Medline]
161. Zhao Q, Ishibashi M, Hiasa K, Tan C, Takeshita A, Egashira K 2004 Essential role of vascular endothelial growth factor in angiotensin II-induced vascular inflammation and remodeling. Hypertension 44:264–270[Abstract/Free Full Text]
162. Imanishi T, Hano T, Nishio I 2004 Angiotensin II potentiates vascular endothelial growth factor-induced proliferation and network formation of endothelial progenitor cells. Hypertens Res 27:101–108[CrossRef][Medline]
163. Fujita M, Hayashi I, Yamashina S, Fukamizu A, Itoman M, Majima M 2005 Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth. Carcinogenesis 26:271–279[Abstract/Free Full Text]
164. Sarlos S, Wilkinson-Berka JL 2005 The renin-angiotensin system and the developing retinal vasculature. Invest Ophthalmol Vis Sci 46:1069–1077[Abstract/Free Full Text]
165. Nagai N, Noda K, Urano T, Kubota Y, Shinoda H, Koto T, Shinoda K, Inoue M, Shiomi T, Ikeda E, Tsubota K, Suda T, Oike Y, Ishida S 2005 Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci 46:1078–1084[Abstract/Free Full Text]
166. Nielsen S, Halliwill JR, Joyner MJ, Jensen MD 2004 Vascular response to angiotensin II in upper body obesity. Hypertension 44:435–441[Abstract/Free Full Text]
167. Caterson ID, Hubbard V, Bray GA, Grunstein R, Hansen BC, Hong Y, Labarthe D, Seidell JC, Smith Jr SC 2004 Prevention Conference VII: Obesity, a worldwide epidemic related to heart disease and stroke: Group III: worldwide comorbidities of obesity. Circulation 110:e476–e483
168. Meigs JB 2003 The metabolic syndrome. Br Med J 327:61–62[Free Full Text]
169. Rajagopalan S, Harrison DG 1996 Reversing endothelial dysfunction with ACE inhibitors. A new trend. Circulation 94:240–243[Free Full Text]
170. Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME 2005 Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens 23:463–473[Medline]
171. Kershaw EE, Flier JS 2004 Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556[Abstract/Free Full Text]
172. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K 2004 Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10:1384–1389[CrossRef][Medline]
173. Lin LY, Lin CY, Su TC, Liau CS 2004 Angiotensin II-induced apoptosis in human endothelial cells is inhibited by adiponectin through restoration of the association between endothelial nitric oxide synthase and heat shock protein 90. FEBS Lett 574:106–110[CrossRef][Medline]
174. Fujimoto M, Masuzaki H, Tanaka T, Yasue S, Tomita T, Okazawa K, Fujikura J, Chusho H, Ebihara K, Hayashi T, Hosoda K, Nakao K 2004 An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3–L1 adipocytes. FEBS Lett 576:492–497[CrossRef][Medline]
175. Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, Kang MH, Ahn TH, Choi IS, Shin EK 2004 Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 110:3687–3692[Abstract/Free Full Text]
176. Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N, Yoshida D, Shimamoto K 2003 Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension 42:76–81[Abstract/Free Full Text]
177. Fortuno A, Rodriguez A, Gomez-Ambrosi J, Fruhbeck G, Diez J 2003 Adipose tissue as an endocrine organ: role of leptin and adiponectin in the pathogenesis of cardiovascular diseases. J Physiol Biochem 59:51–60[Medline]
178. Yasunari K, Maeda K, Nakamura M, Watanabe T, Yoshikawa J, Asada A 2004 Pharmacological and clinical studies with temocapril, an angiotensin converting enzyme inhibitor that is excreted in the bile. Cardiovasc Drug Rev 22:189–198[Medline]
179. Zanchetti A, Ruilope LM 2002 Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from recent controlled randomized trials? J Hypertens 20:2099–2110[CrossRef][Medline]
180. Folli F, Saad MJ, Velloso L, Hansen H, Carandente O, Feener EP, Kahn CR 1999 Crosstalk between insulin and angiotensin II signalling systems. Exp Clin Endocrinol Diabetes 107:133–139[Medline]
181. Giacchetti G, Sechi LA, Rilli S, Carey RM 2005 The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab 16:120–126[CrossRef][Medline]
182. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD 1993 The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462[Abstract/Free Full Text]
183. Arauz-Pacheco C, Parrott MA, Raskin P 2003 Treatment of hypertension in adults with diabetes. Diabetes Care 26(Suppl 1):S80–S82
184. Tuck ML, Bounoua F, Eslami P, Nyby MD, Eggena P, Corry DB 2004 Insulin stimulates endogenous angiotensin II production via a mitogen-activated protein kinase pathway in vascular smooth muscle cells. J Hypertens 22:1779–1785[CrossRef][Medline]
185. Doggrell SA 2003 ACE inhibitors and AT-1-receptor antagonists cooperate in non-diabetic renal disease. Expert Opin Pharmacother 4:1185–1188[CrossRef][Medline]
186. Perez DL, De Wit C, Cohen CD, Nieto E, Molina A, Banas B, Luckow B, Vicente AB, Mampaso F, Schlondorff D 2003 Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice. J Pharmacol Exp Ther 307:275–281[Abstract/Free Full Text]
187. Ushio-Fukai M, Alexander RW 2004 Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 264:85–97[CrossRef][Medline]
188. Marsigliante S, Resta L, Muscella A, Vinson GP, Marzullo A, Storelli C 1996 AT1 angiotensin II receptor subtype in the human larynx and squamous laryngeal carcinoma. Cancer Lett 110:19–27[CrossRef][Medline]
189. Inwang ER, Puddefoot JR, Brown CL, Goode AW, Marsigliante S, Ho MM, Payne JG, Vinson GP 1997 Angiotensin II type 1 receptor expression in human breast tissues. Br J Cancer 75:1279–1283[Medline]
190. Chen L, Re RN, Prakash O, Mondal D 1991 Angiotensin-converting enzyme inhibition reduces neuroblastoma cell growth rate. Proc Soc Exp Biol Med 196:280–283[CrossRef][Medline]
191. Reddy MK, Baskaran K, Molteni A 1995 Inhibitors of angiotensin-converting enzyme modulate mitosis and gene expression in pancreatic cancer cells. Proc Soc Exp Biol Med 210:221–226[CrossRef][Medline]
192. Hii SI, Nicol DL, Gotley DC, Thompson LC, Green MK, Jonsson JR 1998 Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma. Br J Cancer 77:880–883[Medline]
193. Fujimoto Y, Sasaki T, Tsuchida A, Chayama K 2001 Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist. FEBS Lett 495:197–200[CrossRef][Medline]
194. Miyajima A, Kosaka T, Asano T, Asano T, Seta K, Kawai T, Hayakawa M 2002 Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res 62:4176–4179[Abstract/Free Full Text]
195. Fujita M, Hayashi I, Yamashina S, Itoman M, Majima M 2002 Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun 294:441–447[CrossRef][Medline]
196. Greco S, Muscella A, Elia MG, Salvatore P, Storelli C, Mazzotta A, Manca C, Marsigliante S 2003 Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells. J Cell Physiol 196:370–377[CrossRef][Medline]
197. Koh WP, Yuan JM, Van Den Berg D, Lee HP, Yu MC 2005 Polymorphisms in angiotensin II type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis 26:459–464[Abstract/Free Full Text]
198. Uemura H, Ishiguro H, Nakaigawa N, Nagashima Y, Miyoshi Y, Fujinami K, Sakaguchi A, Kubota Y 2003 Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol Cancer Ther 2:1139–1147[Abstract/Free Full Text]
199. Schafer B, Marg B, Gschwind A, Ullrich A 2004 Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival. J Biol Chem 279:47929–47938[Abstract/Free Full Text]
200. Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, Ishii M, Akagi T, Ikeda H, Matsuishi T, Imaizumi T 2003 Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest 112:67–75[CrossRef][Medline]
201. Fischer OM, Giordano S, Comoglio PM, Ullrich A 2004 Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells. J Biol Chem 279:28970–28978[Abstract/Free Full Text]
202. Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JW 1998 Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 352:179–184[CrossRef][Medline]
203. Freitas-Silva M, Pereira D, Coelho C, Bicho M, Lopes C, Medeiros R 2004 Angiotensin I-converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women. Cancer Genet Cytogenet 155:42–46[CrossRef][Medline]
204. Deshayes F, Nahmias C 2005 Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab 16:293–299[CrossRef][Medline]
205. Smith GR, Missailidis S 2004 Cancer, inflammation and the AT1 and AT2 receptors. J Inflamm (Lond) 1:3[CrossRef][Medline]

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