Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload
- 22 June 2004
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 109 (24), 3050-3055
- https://doi.org/10.1161/01.cir.0000130641.08705.45
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 ≈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 α-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase. Conclusions— Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.This publication has 16 references indexed in Scilit:
- Deletion of Ribosomal S6 Kinases Does Not Attenuate Pathological, Physiological, or Insulin-Like Growth Factor 1 Receptor-Phosphoinositide 3-Kinase-Induced Cardiac HypertrophyMolecular and Cellular Biology, 2004
- Ventricular remodeling in heart failure: a credible surrogate endpointJournal of Cardiac Failure, 2003
- Phosphoinositide 3-kinase(p110α) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophyProceedings of the National Academy of Sciences of the United States of America, 2003
- Rapamycin Attenuates Load-Induced Cardiac Hypertrophy in MiceCirculation, 2003
- Akt/Protein Kinase B Promotes Organ Growth in Transgenic MiceMolecular and Cellular Biology, 2002
- SERCA Pump Level is a Critical Determinant of Ca2+Homeostasis and Cardiac ContractilityJournal of Molecular and Cellular Cardiology, 2001
- Rapamycin in transplantation: A review of the evidenceKidney International, 2001
- Rapamycin Inhibits α 1 -Adrenergic Receptor–Stimulated Cardiac Myocyte Hypertrophy but Not Activation of Hypertrophy-Associated GenesCirculation Research, 1997
- Rapamycin Selectively Inhibits Angiotensin II–Induced Increase in Protein Synthesis in Cardiac Myocytes In VitroCirculation Research, 1995
- Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload.Proceedings of the National Academy of Sciences of the United States of America, 1988