(Circulation. 2001;103:1787.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Combined and Individual Mitochondrial HSP60 and HSP10 Expression in Cardiac Myocytes Protects Mitochondrial Function and Prevents Apoptotic Cell Deaths Induced by Simulated Ischemia-Reoxygenation
From the Division of Endocrinology and Metabolism, Department of Medicine (K.M.L., B.L., I.Y.L., W.H.D.), and the Department of Biology (I.E.S.), University of California, San Diego; and the Department of Physiology, Loyola University, Maywood, Ill (R.M.).
Correspondence to Wolfgang H. Dillmann, MD, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0618. E-mail dillmann{at}ucsd.edu
Background—The mitochondrial heat-shock proteins HSP60 and HSP10 form a mitochondrial chaperonin complex, and previous studies have shown that their increased expression exerts a protective effect against ischemic injury when cardiac myocytes are submitted to simulated ischemia. The more detailed mechanisms by which such a protective effect occurs are currently unclear. We wanted to determine whether HSP60 and HSP10 could exert a protection against simulated ischemia and reoxygenation (SI/RO)–induced apoptotic cell death and whether such protection results from decreased mitochondrial cytochrome c release and caspase-3 activation and from the preservation of ATP levels by preservation of the electron transport chain complexes. In addition, we explored whether increased expression of HSP60 or HSP10 by itself exerts a protective effect.
Methods and Results—We overexpressed HSP60 and HSP10 together or separately in rat neonatal cardiac myocytes using an adenoviral vector and then subjected the myocytes to SI/RO. Cell death and apoptosis in myocytes were quantified by parameters such as enzyme release, DNA fragmentation, and caspase-3 activation. Overexpression of the combination of HSP60 and HSP10 and of HSP60 or HSP10 individually protected myocytes against apoptosis. This protection is accompanied by decreases in mitochondrial cytochrome c release and in caspase-3 activity and increases in ATP recovery and activities of complex III and IV in mitochondria after SI/RO.
Conclusions—These results suggest that mitochondrial chaperonins HSP60 and HSP10 in combination or individually play an important role in maintaining mitochondrial integrity and capacity for ATP generation, which are the crucial factors in determining survival of cardiac myocytes undergoing ischemia/reperfusion injury.
Key Words: ischemia • apoptosis • reperfusion
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