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Type 2 Iodothyronine Deiodinase Transgene Expression in the Mouse Heart Causes Cardiac-Specific Thyrotoxicosis¹

Thyroid Division (J.P., R.P., H.T., S.D.C., P.R.L.), Brigham and Women’s Hospital, Harvard Institute of Medicine, Boston, Massachusetts 02115; Department of Internal Medicine and Endocrinology (J.P.), University Medical School of Warsaw, 02–097 Warsaw, Poland; Nuclear Magnetic Resonance Laboratory for Physiological Chemistry (J.H., J.S.I.), Brigham and Women’s Hospital, Boston, Massachusetts; Thyroid Unit (H.K., E.D.A., F.E.W.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: P. Reed Larsen, M.D., FACP, FRCP, Chief, Thyroid Division, Brigham and Women’s Hospital, 560 Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115. E-mail: larsen{at}rascal.med.harvard.edu

Type 2 iodothyronine deiodinase (D₂) catalyzes intracellular 3, 5, 3' triiodothyronine (T₃) production from thyroxine (T₄), and its messenger RNA mRNA is highly expressed in human, but not rodent, myocardium. The goal of this study was to identify the effects of D₂ expression in the mouse myocardium on cardiac function and gene expression. We prepared transgenic (TG) mice in which human D₂ expression was driven by the -MHC promoter. Despite high myocardial D₂ activity, myocardial T₃ was, at most, minimally increased in TG myocardium. Although, plasma T₃ and T₄, growth rate as well as the heart weight was not affected by TG expression, there was a significant increase in heart rate of the isolated perfused hearts, from 284 ±12 to 350 ± 7 beats/min. This was accompanied by an increase in pacemaker channel (HCN2) but not -MHC or SERCA II messenger RNA levels. Biochemical studies and ³¹P-NMR spectroscopy showed significantly lower levels of phosphocreatine and creatine in TG hearts. These results suggest that even mild chronic myocardial thyrotoxicosis, such as may occur in human hyperthyroidism, can cause tachycardia and associated changes in high energy phosphate compounds independent of an increase in SERCA II and -MHC.

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