Project: Research project

Project Details


Numerous studies have demonstrated myocyte apoptosis during myocardial
infarction, ischemia-reperfusion injury, and chronic heart failure.
Despite these observations, the two most critical questions in the field
remain unexplored: 1) What is the precise molecular mechanism of
apoptosis in cardiac myocytes? 2) To what extent does myocyte apoptosis
contribute to myocardial dysfunction in these disease states? The
research program described herein addresses both of these interrelated
questions. To facilitate a molecular genetic analysis, models of
myocardial infarction and ischemia-reperfusion injury have been
developed and characterized in the mouse. Using genetically altered
mice, we have tested the necessity of proteins that mediate apoptosis
in non-cardiac contexts for apoptosis during myocardial infarction.
These studies have shown that one such protein, p53, while present in
ischemic cardiac myocytes and sufficient to induce apoptosis in these
cells, is not required for myocyte apoptosis. This result suggests that
the apoptotic program in complex pathophysiologic states can be
activated by multiple, redundant signaling pathways. In contrast, the
caspases, a family of cysteine proteases, are components of the final
common pathway for apoptosis in all metazoan cells from worm to mammal.
Indeed we have shown that pharmacologic blockade of these enzymes
markedly inhibits myocyte apoptosis during myocardial infarction in
vivo. The potential significance of this result is two-fold: First,
caspase inhibition may provide a direct means to determine the
contribution of myocyte apoptosis to myocardial dysfunction. Second,
caspase inhibition may provide a new therapeutic approach to ischemic
heart disease and heart failure. We now propose to deepen our
understanding of the mechanism and significance of cardiac myocyte
apoptosis through the following specific aims: 1. To determine which
caspases are expressed in adult cardiac myocytes and undergo proteolytic
activation during myocardial infarction and ischemia-reperfusion injury.
2. To block myocyte apoptosis in these ischemic syndromes using caspase
inhibition. Complementary pharmacologic (peptide pseudosubstrates) and
transgenic (overexpression of a dominant caspase inhibitor) approaches
will be employed. 3. To determine the contribution of apoptosis to
changes in myocardial structure and function during and after infarction
and ischemia-reperfusion injury. Using caspase inhibition, the
contribution of myocyte apoptosis to infarct size, ventricular
remodeling, and contractile dysfunction will be determined. These
studies will increase our understanding of the mechanism of cardiac
myocyte apoptosis and its role in the pathogenesis of ischemic heart
Effective start/end date8/1/983/31/15


  • Cardiology and Cardiovascular Medicine
  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Immunology


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