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Circulation. 2004 Jun 22;109(24):3050-5. Epub 2004 Jun 7.

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

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1
Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, Mass 02215, USA. jmcmulle@bidmc.harvard.edu

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.

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