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Glycated Fibroblast Growth Factor-2 Is Quickly Produced in Vitro upon Low-Millimolar Glucose Treatment and Detected in Vivo in Diabetic Mice

Dipartimento di Ematologia Oncologia e Medicina Molecolare (F.F., C.P.), Istituto Superiore di Sanità, I-00161 Roma, Italy; Laboratorio di Patologia Vascolare (F.F., D.D., K.R., M.C.C., A.F.), and Laboratorio di Biologia Molecolare e Cellulare (G.Z.), Istituto Dermopatico dell’Immacolata-IDI, Istituto di Ricovero e Cura a Carattere Scientifico, I-00167 Roma, Italy; Dipartimento di Scienza degli Alimenti (V.F., C.M.), Università di Napoli "Federico II", I-80055 Portici, Italy; Dipartimento di Biochimica e Biofisica (R.R.), Seconda Università di Napoli, I-80138 Napoli, Italy; Istituto di Scienze dell’Alimentazione (V.C.), Consiglio Nazionale delle Ricerche, I-83100 Avellino, Italy; and Dipartimento di Anatomia Umana e Istologia (D.R.), Policlinico, I-70124 Bari, Italy

Address all correspondence and requests for reprints to: Francesco Facchiano, M.D., Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy. E-mail: facchian{at}iss.it.

Angiogenesis impairment in hyperglycemic patients represents a leading cause of severe vascular complications of both type-1 and -2 diabetes mellitus (DM). Angiogenesis dysfunction in DM is related to glycemic control; however, molecular mechanisms involved are still unclear. Fibroblast growth factor-2 (FGF-2) is a potent angiogenic factor and, according to previous evidence, may represent a key target of molecular modifications triggered by high-sugar exposure. Therefore, the purpose of this study was to investigate whether short incubation with hyperglycemic levels of glucose affected FGF-2 and whether glucose-modified FGF-2 was detectable in vivo. Biochemical analyses carried out with SDS-PAGE, fluorescence emission, mass-spectrometry, immunoblot, and competitive ELISA experiments demonstrated that human FGF-2 undergoes a rapid and specific glycation upon 12.5–50 mM glucose exposure. In addition, FGF-2 exposed for 30 min to 12.5 mM glucose lost mitogenic and chemotactic activity in a time- and dose-dependent manner. Under similar conditions, binding affinity to FGF receptor 1 was dramatically reduced by 20-fold, as well as FGF receptor 1 and ERK-1/2 phosphorylation, and FGF-2 lost about 45% of angiogenic activity in two different in vivo angiogenic (Matrigel and chorioallantoic-membrane) assays. Such glucose-induced modification was specific, because other angiogenic growth factors, namely platelet-derived growth factor BB and placental-derived growth factor were not significantly or markedly less modified. Finally, for the first time, glycated-FGF-2 was detected in vivo, in tissues from hyperglycemic nonobese diabetic mice, in significantly higher amounts than in normoglycemic mice. In conclusion, hyperglycemic levels of glucose may strongly affect FGF-2 structure and impair its angiogenic features, and endogenous glycated-FGF-2 is present in diabetic mice, indicating a novel pathogenetic mechanism underlying angiogenesis defects in DM.

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