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Chronic Cardiac-Specific Thyrotoxicosis Increases Myocardial ß-Adrenergic Responsiveness

Thyroid Section, Division of Endocrinology, Diabetes and Hypertension (S.D.C.-B., B.W.K., J.W.H., R.S.R., A.C.B., P.R.L.); Cardiology Division of the Brigham and Women’s Hospital (J.X.Z., U.M.); Harvard Medical School, Boston, Massachusetts 02115; and Department of Endocrine- and Behavioral Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary

Address all correspondence and requests for reprints to: P. Reed Larsen, M.D., Division of Endocrinology, Diabetes and Hypertension, Brigham & Women’s Hospital, 77 Avenue Louis Pasteur, Room 550, Boston, Massachusetts 02115.

Whereas many cardiac symptoms of thyrotoxicosis resemble those of the hyperadrenergic state, circulating catecholamines are reduced or normal in this condition. To test the hypothesis that the thyrotoxic heart is hypersensitive to catechol-amines, we studied ß-adrenergic signaling in a transgenic (TG) mouse in which the human type 2 iodothyronine deiodinase (D2) gene is expressed in myocardium. Because D2 converts T₄ to T₃, the active form of thyroid hormone, the D2 TG mouse exhibits mild, chronic thyrotoxicosis that is limited to the myocardium. In the current study, we determined that cAMP accumulation in response to either norepinephrine or forskolin treatment was increased in isolated ventricular myocardiocytes and membrane-enriched fractions prepared from these D2 TG hearts as compared with wild type. This increase in adenylyl cyclase (AC) V_max could not be explained by changes in AC isoform expression or changes in the long or short forms of stimulatory G-protein Gs, which were approximately 10% decreased in D2 TG membranes. However, Western analysis and ADP-ribosylation studies suggest that the increase in AC V_max is mediated by a decrease in the expression of inhibitory G proteins (Gi-3 and/or Go). These data suggest that cardiac thyrotoxicosis leads to increased ß-adrenergic responsiveness of cardiomyocytes via alterations in the regulatory G-protein elements of the AC membrane complex.

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