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(Circulation Research. 2007;100:645.)
© 2007 American Heart Association, Inc.

Molecular Medicine

A Role for Caspase-1 in Heart Failure

Sabine Merkle, Stefan Frantz, Michael P. Schön, Johann Bauersachs, Monika Buitrago, Robert J.A. Frost, Eva M. Schmitteckert, Martin J. Lohse, Stefan Engelhardt

From the Rudolf Virchow Center (S.M., M.P.S., M.B., R.J.A.F., S.E.), Deutsche Forschungsgemeinschaft-Research Center for Experimental Biomedicine; Department of Internal Medicine (S.F., J.B.); Department of Dermatology, Venereology and Allergology (M.P.S.); and Institute of Pharmacology and Toxicology (E.S., M.J.L.), University of Wuerzburg, Germany.

Correspondence to Stefan Engelhardt, MD PhD, Rudolf Virchow Center, DFG-Research Center for Experimental Biomedicine, University of Wuerzburg, Versbacher Strasse 9, 97078 Wuerzburg, Germany. E-mail stefan.engelhardt{at}virchow.uni-wuerzburg.de

Apoptosis of cardiomyocytes is increased in heart failure and has been implicated in disease progression. The activation of "proapoptotic" caspases represents a key step in cardiomyocyte apoptosis. In contrast, the role of "proinflammatory" caspases (caspases 1, 4, 5, 11, 12) is unclear. Here, we study the cardiac function of caspase-1. Gene array analysis in a murine heart failure model showed upregulation of myocardial caspase-1. In addition, we found increased expression of caspase-1 protein in murine and human heart failure. Mice with cardiomyocyte-specific overexpression of caspase-1 developed heart failure in the absence of detectable formation of interleukin (IL)-1ß or IL-18 and inflammation. Transgenic caspase-1 induced primary cardiomyocyte apoptosis before structural and molecular signs of myocardial remodeling occurred. In contrast, deletion of endogenous caspase-1 was beneficial in the setting of myocardial infarction–induced heart failure. Furthermore, caspase-1–deficient mice were protected from ischemia/reperfusion-induced cardiomyocyte apoptosis. Studies in primary rat cardiomyocytes indicated that caspase-1 induces cardiomyocyte apoptosis primarily through activation of caspases-3 and -9. In contrast to previous findings, which imply a proinflammatory role of caspase-1, these data suggest a primary proapoptotic role for caspase-1 in cardiomyocytes. Our findings support a functional role for caspase-1–mediated myocardial apoptosis contributing to the progression of heart failure.

Key Words: caspase-1 • transgenic mouse • heart failure

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