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.