© 1999 American Heart Association, Inc.
Cellular Biology |
The Mitochondrial Apoptotic Pathway Is Activated by Serum and Glucose Deprivation in Cardiac Myocytes
From the Departments of Medicine (Cardiology) and Cell Biology (S.B., S.M., A.L.W., R.N.K.), Albert Einstein College of Medicine, Bronx, NY; Division of Endocrinology (V.L.C., A.D.), Northwestern University Medical Center, Chicago, Ill; and Idun Pharmaceuticals (A.S.), La Jolla, Calif. S.B.'s present address is Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Correspondence to Richard N. Kitsis, Departments of Medicine (Cardiology) and Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. E-mail kitsis{at}aecom.yu.edu
Abstract—Many cell types undergo apoptosis under conditions of ischemia. Little is known, however, about the molecular pathways that mediate this response. A cellular and biochemical approach to elucidate such signaling pathways was undertaken in primary cultures of cardiac myocytes, a cell type that is especially sensitive to ischemia-induced apoptosis. Deprivation of serum and glucose, components of ischemia in vivo, resulted in myocyte apoptosis, as determined by nuclear fragmentation, internucleosomal cleavage of DNA, and processing of caspase substrates. These manifestations of apoptosis were blocked by zVAD-fmk, a peptide caspase inhibitor, indicating that caspase activity is necessary for the progression of apoptosis in this model. In contrast to control cells, apoptotic myocytes exhibited cytoplasmic accumulation of cytochrome c, indicating release from the mitochondria. Furthermore, both caspase-9 and caspase-3 were processed to their active forms in serum-/glucose-deprived myocytes. Caspase processing, but not cytochrome c release, was inhibited by zVAD-fmk, placing the latter event upstream of caspase activation. This evidence demonstrates that components of ischemia activate the mitochondrial death pathway in cardiac myocytes.
Key Words: apoptosis • cysteine proteinase • cytochrome c • mitochondria • ischemia
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