Project: Research project

Project Details



(Adapted from the applicant's abstract) Numerous studies have demonstrated
the occurrence of myocyte apoptosis during myocardial infarction,
ischemia-reperfusion injury, and heart failure. Despite these observations,
the two most critical questions in the field remain poorly understood: 1.
What is the precise mechanism of apoptosis in cardiac myocytes? 2. To what
extent does myocyte apoptosis contribute to the changes in myocardial
structure and function that characterize these disease states? The research
program described herein addresses both of these interrelated questions in
the case of chronic heart failure. The applicant's laboratory has
previously demonstrated that the signals that elicit cardiac myocyte
apoptosis in complex pathophysiologic states are, not unexpectedly,
transduced via multiple pathways, inhibition of any one of which is
insufficient to abrogate apoptosis. In contrast, the caspases, a novel
family of cysteine proteases, constitute the final common pathway for
apoptosis in all metazoan cells from worm to mammal. Indeed the applicant's
preliminary data show that blockade of caspase activation markedly inhibits
cardiac myocyte apoptosis in vivo. The significance of this result is that
caspase inhibition provides a means to determine the contribution of myocyte
apoptosis to the pathogenesis of heart failure. Accordingly, the objective
of this application is to delineate the roles of caspase activation and
myocyte apoptosis in heart failure. This objective will be accomplished
through the following specific aims: 1. To determine which of the caspases
are activated in cardiac myocytes by pro-apoptotic component stimuli of
heart failure and whether caspase activation is necessary for these stimuli
to kill cardiac myocytes. 2. To determine the effect of inhibiting myocyte
apoptosis on cardiac structure and function during experimental heart
failure in vivo. 3. To determine the sufficiency of caspase activation to
induce cardiomyopathy in vivo. Taken together, this research program will
define the role of caspase activation in cardiac myocyte apoptosis and the
role of cardiac myocyte apoptosis itself in the pathogenesis of chronic
heart failure. In so doing, these studies may provide the conceptual
framework for novel heart failure therapies based on apoptosis inhibition.
Effective start/end date9/30/986/30/08


  • Cardiology and Cardiovascular Medicine
  • Medicine(all)


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