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Mechanisms of myocardial ischemic preconditioning are age related: PKC- does not play a requisite role in old rabbits

¹Departments of Emergency Medicine and Anesthesiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655; and ²Heart Institute, Good Samaritan Hospital, and Department of Medicine, Section of Cardiology, University of Southern California, Los Angeles, California 90017

Submitted 23 April 2003 ; accepted in final form 4 August 2003

Data obtained from adult cohorts have implicated activation/translocation of protein kinase C (PKC)- as an important cellular mediator of myocardial infarct size reduction with ischemic preconditioning (PC). Age-related alterations in cellular signaling may, however, confound the extrapolation of mechanistic insight derived from adults to the aging population, the specific subset in which cardioprotection is undoubtedly most relevant. Accordingly, our aim was to investigate the role of PKC- as a mediator of infarct size reduction with PC in old vs. adult rabbits. In protocol 1, we assessed the effect of PKC- translocation inhibitor peptide (PKC--TIP) and the pan-PKC inhibitor chelerythrine on infarct size reduction with PC in adult and 4-yr-old rabbits, a population previously shown to exhibit definitive hallmarks of cardiovascular aging. Rabbits received 5 min of PC ischemia or a matched control period followed by 30 min of coronary artery occlusion and 3 h of reperfusion, with infarct size (delineated by tetrazolium staining) serving as the primary endpoint. In protocol 2, we obtained insight (by Western immunoblotting) into the subcellular redistribution of PKC- in response to the 5-min PC stimulus in adult and old rabbits. In adults, infarct size reduction with PC was abrogated by both PKC--TIP and chelerythrine. However, in old rabbits, 1) PC-induced cardioprotection was maintained despite inhibitor treatment and 2) brief PC ischemia was not associated with activation/translocation of PKC-. Thus the mechanisms responsible for PC are age related in the rabbit heart, with no apparent, requisite role of PKC- in aging animals.

myocardial ischemia; myocardial infarction; signal transduction; protein kinase C

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