Abstract
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)-1beta
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.
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