Proceedings of the National Academy of Sciences of the United States of America
Geisel School of Medicine
Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca(2+) cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.
Trivieri MG, Oudit GY, Sah R, Kerfant BG, Sun H, Gramolini AO, Pan Y, Wickenden AD, Croteau W, Morreale de Escobar G, Pekhletski R, St Germain D, Maclennan DH, Backx PH. Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6043-8. doi: 10.1073/pnas.0601072103. Epub 2006 Apr 4. PMID: 16595628; PMCID: PMC1426242.
Dartmouth Digital Commons Citation
Trivieri, Maria G.; Oudit, Gavin Y.; Sah, Rajan; Kerfant, Benoit-Giles; Sun, Hui; Gramolini, Anthony O.; Pan, Yan; Wickenden, Alan D.; and Croteau, Walburga, "Cardiac-Specific Elevations in Thyroid Hormone Enhance Contractility and Prevent Pressure Overload-Induced Cardiac Dysfunction" (2006). Dartmouth Scholarship. 1397.