Whereas many cardiac symptoms of thyrotoxico- sis 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 -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 deter- mined that cAMP accumulation in response to ei- ther norepinephrine or forskolin treatment was in- creased 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) Vmax 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% de- creased in D2 TG membranes. However, Western analysis and ADP-ribosylation studies suggest that the increase in AC Vmax is mediated by a decrease in the expression of inhibitory G proteins (Gi -3 and/or Go ). These data suggest that cardiac thy- rotoxicosis leads to increased -adrenergic re- sponsiveness of cardiomyocytes via alterations in the regulatory G-protein elements of the AC membrane complex.
Chronic Cardiac-Specific Thyrotoxicosis Increases Myocardial – Adrenergic Responsiveness.
Suzy D. Carvalho-Bianco, Brian W. Kim, Julie X. Zhang, John W. Harney, Roge ́ Rio S. Ribeiro, Balazs Gereben, Antonio C. Bianco, Ulrike Mende, And P. Reed Larsen. Molecular Endocrinology. July, 2004.doi: 10.1210/me.2003-0125