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(Circulation Research. 2005;96:1103.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Proapoptotic Effects of Caspase-1/Interleukin-Converting Enzyme Dominate in Myocardial Ischemia

Faisal M. Syed, Harvey S. Hahn, Amy Odley, Yiru Guo, Jesus G. Vallejo, Roy A. Lynch, Douglas L. Mann, Roberto Bolli, Gerald W. Dorn, II

From the Department of Medicine (F.M.S., H.S.H., A.O., R.A.L., G.W.D), University of Cincinnati, Cincinnati, Ohio; the Winters Center for Heart Failure Research (D.L.M., J.G.V.), Baylor College of Medicine, Houston, Tex; and the Institute of Molecular Cardiology (R.B., Y.G.), University of Louisville, Louisville, Ken.

Correspondence to G.W. Dorn II, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH 45267-0542. E-mail dorngw{at}ucmail.uc.edu

Caspase-1/interleukin-converting enzyme (ICE) is a cysteine protease traditionally considered to have importance as an inflammatory mediator, but not as an apoptotic effector. Because of the dual functions of this caspase, the pathophysiological impact of its reported upregulation in hypertrophy and heart failure is not known. Here, the consequences of increased myocardial expression of procaspase-1 were examined on the normal and ischemically injured heart. In unstressed mouse hearts with a 30-fold increase in procaspase-1 content, unprocessed procaspase-1 was well tolerated, without detectable pathology. Cardiomyocyte processing and activation of caspase-1 and caspase-3 occurred after administration of endotoxin or with transient myocardial ischemia. In post-ischemic hearts, procaspase-1 overexpression was associated with strikingly increased cardiac myocyte apoptosis in the peri- and noninfarct regions and with 50% larger myocardial infarctions. Tissue culture studies revealed that procaspase-1 processing/activation is stimulated by hypoxia, and that caspase-1 acts in synergy with hypoxia to stimulate caspase-3 mediated apoptosis without activating upstream caspases. These data demonstrate that the proapoptotic effects of caspase-1 can significantly impact the myocardial response to ischemia and suggest that conditions in which procaspase-1 in the heart is increased may predispose to apoptotic myocardial injury under conditions of physiological stress.

Key Words: apoptosis • myocardial infarction • myocardial ischemia • caspase

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