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(Circulation. 2004;109:3050-3055.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload

Julie R. McMullen, PhD; Megan C. Sherwood, MBBS, FRACP; Oleg Tarnavski, MD; Li Zhang, MS; Adam L. Dorfman, MD; Tetsuo Shioi, MD, PhD; Seigo Izumo, MD

From the Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center (J.R.M., O.T., L.Z., T.S., S.I.), and Department of Cardiology, Boston Children’s Hospital (M.C.S., A.L.D.), Boston, Mass. Dr Shioi is now at the Department of Internal Medicine and Cardiology, Kitasato University, School of Medicine, Sagamihara, Japan.

Correspondence to Julie McMullen, PhD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail jmcmulle{at}bidmc.harvard.edu

Received August 29, 2003; de novo received November 10, 2003; revision received March 15, 2004; accepted March 15, 2004.

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 -myosin heavy chain and sarcoplasmic reticulum Ca²⁺ ATPase.

Conclusions— Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.

Key Words: hypertrophy • heart failure • signal transduction

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