Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload Academic Article uri icon

abstract

  • 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 approximately 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 x kg(-1) x 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.

authors

  • McMullen, Julie R
  • Sherwood, Megan C
  • Tarnavski, Oleg
  • Zhang, Li
  • Dorfman, Adam L
  • Shioi, Tetsuo
  • Izumo, Seigo

publication date

  • June 22, 2004

has subject area