on March 17, 2003
Circulation. 2003
Published online before print March 17, 2003, doi: 10.1161/01.CIR.0000057979.36322.88
Published online before print March 17, 2003, doi: 10.1161/01.CIR.0000057979.36322.88
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Submitted on December 28, 2001
From the Cardiovascular Division, Department of Medicine (T.S., J.R.M., O.T., K.C., W.J.M., S.I.) and Department of Radiology (K.C., W.J.M.), Beth Israel Deaconess Medical Center, and the Department of Cardiology (M.C.S.), Boston Children's Hospital, Boston, Mass. * To whom correspondence should be addressed. E-mail: sizumo{at}bidmc.harvard.edu.
Background--Cardiac hypertrophy, or an increase in heart size, is an important risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) is a component of the insulin-phosphoinositide 3-kinase pathway, which is known to play a critical role in the determination of cell, organ, and body size. Methods and Results--To examine the role of mTOR in load-induced cardiac hypertrophy, we administered rapamycin, a specific inhibitor of mTOR, to mice with ascending aortic constriction. Activity of p70 ribosomal S6 kinase 1 (S6K1), an effector of mTOR, was increased by 3.8-fold in the aortic-constricted heart. Pretreatment of mice with 2 mg · kg-1 · d-1 of rapamycin completely suppressed S6K1 activation and S6 phosphorylation in response to pressure overload. The heart weight/tibial length ratio of vehicle-treated aortic-banded mice was increased by 34.4±3.6% compared with vehicle-treated sham-operated mice. Rapamycin suppressed the load-induced increase in heart weight by 67%. Attenuation of cardiac hypertrophy by rapamycin was associated with attenuation of the increase in myocyte cell size induced by aortic constriction. Rapamycin did not cause loss of body weight, lethality, or left ventricular dysfunction. Conclusions--mTOR or its target(s) seems to play an important role in load-induced cardiac hypertrophy. Because systemic administration of rapamycin has been used successfully for the treatment of transplant rejection in clinical practice, it may be a useful therapeutic modality to suppress cardiac hypertrophy in patients.
Revised on December 10, 2002
Accepted on December 17, 2002
Rapamycin Attenuates Load-Induced Cardiac Hypertrophy in Mice
Tetsuo Shioi MD, PhD,
Key words: hypertrophy • heart failure • signal transduction
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