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Acute PKC y inhibition limits ischaemia–reperfusion injury in the aged rat heart: Role of GSK-3 h

Objective: Age is a leading risk factor for the development of ischaemic heart disease and failure. However, the efficacy of cardioprotective strategies designed to rescue the aged myocardium remains controversial. We have previously demonstrated increased levels of basal cardiac protein kinase C y (PKC y ) with ageing, a well-known mediator of apoptotic cell death following ischaemia and reperfusion (I/R) in adult hearts. Our objective was to determine the contribution of PKC y signaling mechanisms to reperfusion injury in the aged heart using local delivery of a novel PKC y inhibitory peptide (KID1-1). Methods: Contractile responses were assessed in hearts isolated from adult (4 months, n =38) and aged (24 months, n =45) male Fisher 344 rats treated with either KID1-1 (500 nM) or Tat vehicle peptide (500 nM) upon reperfusion for 10 min following 31-min global ischaemia. Results: Recovery of left ventricular (LV) developed pressure was significantly improved by KID1-1 and associated with smaller infarct size in 24 months vs. age-matched controls ( p <0.005). We also observed significant reductions in DNA laddering and cytochrome c and caspase 3 levels in aged hearts treated with KID1-1. Interestingly, KID1-1 attenuated mitochondrial and nuclear PKC y levels during reperfusion in aged vs. age-matched controls ( p <0.01). Further, increases in mitochondrial phosphorylated glycogen synthase kinase-3 h (pGSK-3 h ) levels were hastened in aged and adult hearts following KID1-1 ( p <0.05), increasing the pGSK-3 h /GSK-3 h ratio. Conclusions: These results provide novel evidence for cardioprotection through acute PKC y inhibition in aged rat heart following I/R. Our results also suggest, for the first time, a key role for mitochondrial GSK-3 h as a cellular basis for the protection associated with PKC y inhibition with ageing. D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.