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Departments of 1 Medicine (Molecular Cardiology), 2 Cell Biology, and 5 Pathology, Albert Einstein College of Medicine, Bronx, New York 10461; 3 Division of Cardiovascular Research, St. Elizabeth's Medical Center, Boston, Massachusetts 02135; and 4 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130
Fas is a widely
expressed cell surface receptor that can initiate apoptosis
when activated by its ligand (FasL). Whereas Fas abundance on cardiac
myocytes increases in response to multiple pathological stimuli, direct
evidence supporting its role in the pathogenesis of heart disease is
lacking. Moreover, controversy exists even as to whether Fas activation
induces apoptosis in cardiac myocytes. In this study, we show
that adenoviral overexpression of FasL, but not 
-galactosidase,
results in marked apoptosis both in cultures of primary
neonatal cardiac myocytes and in the myocardium of intact adult rats.
Myocyte killing by FasL is a specific event, because it does not occur
in lpr (lymphoproliferative) mice that lack functional Fas.
To assess the contribution of the Fas pathway to myocardial infarction
(MI) in vivo, lpr mice were subjected to 30 min of
ischemia followed by 24 h of reperfusion. Compared with
wild-type mice, lpr mice exhibited infarcts that were 62.3%
smaller with 63.8% less myocyte apoptosis. These data provide
direct evidence that activation of Fas can induce apoptosis in
cardiac myocytes and that Fas is a critical mediator of MI due to
ischemia-reperfusion in vivo.
apoptosis; death receptor pathway; genetically altered mice
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