Type 2 iodothyronine deiodinase transgene expression in the mouse heart causes cardiac-specific thyrotoxicosis

Type 2 iodothyronine deiodinase (D-2) catalyzes intracellular 3, 5, 3' trii odothyronine (T-3) production from thyroxine (T-4), and its messenger RNA m RNA is highly expressed in human, but not rodent, myocardium. The goal of t his study was to identify the effects of D-2 expression in the mouse myocar dium on cardiac function and gene expression. We prepared transgenic (TG) m ice in which human D-2 expression was driven by the alpha -MHC promoter. De spite high myocardial D-2 activity, myocardial T-3 was, at most, minimally increased in TG myocardium. Although, plasma T-3 and T-4, growth rate as we ll as the heart weight was not affected by TG expression, there was a signi ficant increase in heart rate of the isolated perfused hearts, from 284 +/- 12 to 350 +/- 7 beats/min. This was accompanied by an increase in pacemake r channel (HCN2) but not alpha -MHC or SERCA II messenger RNA levels. Bioch emical studies and P-31-NMR spectroscopy showed significantly lower levels of phosphocreatine and creatine in TG hearts. These results suggest that ev en mild chronic myocardial thyrotoxicosis, such as may occur in human hyper thyroidism, can cause tachycardia and associated changes in high energy pho sphate compounds independent of an increase in SERCA II and alpha -MHC.