© 2000 American Heart Association, Inc.
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Toward Antiapoptosis as a New Treatment Modality
From the Department of Cardiology (A.H.), University of Heidelberg, Germany, and Cardiovascular Division (S.I.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.
Correspondence to Seigo Izumo, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave (Room SL-201), Boston, MA 02215. E-mail sizumo@caregroup.harvard.edu
Key Words: apoptosis • myocyte • therapy • signal transduction
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Introduction |
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Despite successful new treatment strategies developed in the past few decades aimed at different pathomechanisms of myocardial disease,1 morbidity and mortality due to heart failure and its complications remain a clinical reality. Among the treatment strategies available, the maintenance of contractile mass that is determined by the number of myocytes and the degree of cellular hypertrophy is a major goal in the therapy of cardiac disease. However, increasing contractile mass by myocardial hypertrophy is associated with increased risks of vulnerability to ischemia, arrhythmias, and the transition to heart failure. Recent evidence that apoptosis of cardiac myocytes is a feature in several myocardial disease states, including ischemic heart disease and congestive heart failure (for review, see Reference 22 ), has raised hopes that inhibition of myocyte apoptosis could prevent or slow the loss of contractile cells and thus provide a new target in a multimodal therapeutic approach to cardiac disease.
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Targets for Intervention |
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In apoptotic cell death, in contrast to necrotic (oncotic) cell death, a proapoptotic stimulus initiates a cell-autonomous cascade of events that finally leads to the activation of common apoptotic effector mechanisms that seem essentially uniform in most cell lineages and involve the activation of caspases, an apoptosis-specific endonuclease, and the apoptosis-inducing factor (Figure 1
).2 3 4 5 Regulation of the
apoptotic effector machinery is complex and involves regulatory
proteins that specifically regulate apoptosis (eg, B-cell
lymphoma [Bcl]–2 family proteins or inhibitor of
apoptosis proteins [IAPs]) in addition to signaling pathways
that mediate several other cellular responses (eg, extracellular
signal–regulated kinase [ERK], stress-activated protein
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