Rapamycin Prevents Thyroid Hormone-Induced Cardiac Hypertrophy

Abstract

Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Although THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or whether it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures treated with THs to test whether mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T 4 for 3 d, 1 wk, 2 wk, or 1 month with either placebo, T 4 (50 g/100 g body weight⅐d), rapamycin (200 g/100 g body weight⅐d) or T 4 /rapamycin by sc slow-release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T 3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/ mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy. (Endocrinology 148: 3477-3484, 2007)

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

“…Hypertrophic cells arrested in cell cycle undergo an increase in protein synthesis. 28,[37][38][39] Cell cycle progression is related to protein synthesis during cell proliferation. 40,41) Thus, cell cycle arrest can be accompanied by depressed protein synthesis in H 2 O 2 -treated H9c2 cells.…”

The role of autophagy in the heart

“…Knockdown of Atg7 by Ad-Atg7-RNAi inhibits autophagy in rat neonatal cardiomyocytes and then induces cardiomyocyte hypertrophy with typical characteristics. 29 Rapamycin, a potent activator of autophagy, prevents cardiac hypertrophy induced by thyroid hormone treatment, 35 or aortic banding, 36 and regresses existing cardiac hypertrophy. 37 These suggest that a decrease in autophagy at the hypertrophied state facilitates cardiac hypertrophic response.…”

Recycle or die: The role of autophagy in cardioprotection

“…For instance, Dammrich and Pfeifer observed that cardiac hypertrophy induced by aortic constriction led to inhibition of autophagy in cardiac myocytes undergoing hypertrophy and proposed that the inhibition of degradation was important in growing myocytes since autophagy-mediated protein degradation antagonizes cell growth [13]. Rapamycin, a potent activator of autophagy, was demonstrated to prevent cardiac hypertrophy induced by thyroid hormone treatment [48] or aortic banding [49]. McMullen et al found that rapamycin treatment was even able to regress already established cardiac hypertrophy induced by pressure overload and improve cardiac function [50].…”