Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload

Background - Rapamycin is a specific inhibitor of the mammalian target of rapamycin ( mTOR). We recently reported that administration of rapamycin before exposure to ascending aortic constriction significantly attenuated the load-induced increase in heart weight by approximate to 70%. Methods and Results - To examine whether rapamycin can regress established cardiac hypertrophy, mice were subjected to pressure overload ( ascending aortic constriction) for 1 week, echocardiography was performed to verify an increase in ventricular wall thickness, and mice were given rapamycin ( 2 mg . kg(-1) . d(-1)) for 1 week. After 1 week of pressure overload ( before treatment), 2 distinct groups of animals became apparent: ( 1) mice with compensated cardiac hypertrophy ( normal function) and ( 2) mice with decompensated hypertrophy ( dilated with depressed function). Rapamycin regressed the pressure overload - induced increase in heart weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and 41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular end-systolic dimensions, fractional shortening, and ejection fraction in mice with decompensated cardiac hypertrophy. Rapamycin also altered the expression of some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase. Conclusions - Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.