(Circulation. 2000;102:915.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Involvement of CD95/Apo1/Fas in Cell Death After Myocardial Ischemia
From the German Cancer Research Center (I.J., K.M.D.) and the II. Institute of Physiology (A.M.-V., J.S.), Heidelberg; the Pediatric Hospital, University of Ulm (I.J., K.M.D.); and Internal Medicine I, Klinikum Großhadern (C.K., P.B.), and the Institute for Surgical Research, University of Munich (H.H.), Munich, Germany. The first 2 authors contributed equally to this work.
Background—The death of cardiac cells during ischemia and reperfusion is partially mediated by apoptosis, as seen, eg, in autopsy material of patients after acute myocardial infarction.
Methods and Results—To study the role of CD95/Fas/Apo1 for
induction of postischemic cell death, we used an
ischemia/reperfusion model of isolated rat and mouse hearts in
Langendorff perfusion. In this model, caspase-dependent
apoptosis occurred during postischemic reperfusion.
Moreover, soluble CD95 ligand/Fas ligand was released by the
postischemic hearts early after the onset of reperfusion.
In addition, this ligand was synthesized de novo under these
circumstances. Similar findings were observed for other
"death-inducing" ligands, such as tumor necrosis factor (TNF)-
and TNF-related apoptosis-inducing ligand. In primary adult rat
myocyte culture, hypoxia and reoxygenation
caused a marked increase in sensitivity to the apoptotic
effects of CD95 ligand. Isolated hearts from mice lacking functional
CD95 (lpr) display marked reduction in cell death after
ischemia and reperfusion compared with wild-type controls.
Conclusions—These data suggest that CD95/Apo1/Fas is directly involved in cell death after myocardial ischemia. The CD95 system might thus represent a novel target for therapeutic prevention of postischemic cell death in the heart.
Key Words: ischemia • reperfusion • apoptosis • genes
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