Published Online
on November 24, 2003

A more recent version of this article appeared on December 16, 2003

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Submitted on March 4, 2003
Revised on August 8, 2003
Accepted on August 8, 2003

Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of Gq Transgenic Mice

Yukihiro Hayakawa MD, PhD, Madhulika Chandra MD, Wenfeng Miao MD, PhD, Jamshid Shirani MD, Joan Heller Brown PhD, Gerald W. Dorn II MD, Robert C. Armstrong PhD, and Richard N. Kitsis MD^*

From the Program in Molecular Cardiology, Department of Medicine (Y.H., M.C., W.M., J.S., R.N.K.), and the Department of Cell Biology (Y.H., R.N.K.), Albert Einstein College of Medicine, Bronx, NY; the Department of Pharmacology, University of California San Diego, La Jolla (J.H.B.); the Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio (G.W.D.); and Idun Pharmaceuticals, San Diego, Calif (R.C.A.).

^* To whom correspondence should be addressed. E-mail: kitsis{at}aecom.yu.edu.

Background--Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Gq exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Gq peripartum cardiomyopathy model.

Methods and Results--The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gq mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3-like activity (86.5%; P<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9±0.3% to 0.2±0.1% (P<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7±0.1 mm; IDN-1965, 4.2±0.1 mm; P<0.01), fractional shortening (vehicle, 30.7±1.2%; IDN-1965, 38.9±1.0%; P<0.01), positive (vehicle, 3972±412; IDN-1965, 5870±295; P<0.01) and negative (vehicle, 2365±213; IDN-1965, 3413±201; P<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died; P<0.05).

Conclusions--Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Gq mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.

Key words: apoptosis • caspases • cardiomyopathy

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Apoptosis Inhibitors for Heart Disease

Keith A. Webster and Nanette H. Bishopric
Circulation 2003 108: 2954-2956. [Extract] [Full Text]

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