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Cardiovascular Research 2006 70(2):325-334; doi:10.1016/j.cardiores.2006.02.009
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Copyright © 2006, European Society of Cardiology

Acute PKC{delta} inhibition limits ischaemia–reperfusion injury in the aged rat heart: Role of GSK-3β

John C. Kostyaka, J. Craig Huntera and Donna H. Korzicka,b,*

aIntercollege Program in Physiology, The Pennsylvania State University, University Park, PA 16802, United States
bThe Department of Kinesiology, The Pennsylvania State University, University Park, PA 16802, United States

* Corresponding author. 106 Noll Laboratory, The Pennsylvania State University, University Park, PA 16802, USA. Tel.: +1 814 865 5679; fax: +1 814 865 4602. Email address: dhk102{at}psu.edu

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{delta} (PKC{delta}) 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{delta} signaling mechanisms to reperfusion injury in the aged heart using local delivery of a novel PKC{delta} 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{delta} levels during reperfusion in aged vs. age-matched controls (p<0.01). Further, increases in mitochondrial phosphorylated glycogen synthase kinase-3β (pGSK-3β) levels were hastened in aged and adult hearts following KID1-1 (p<0.05), increasing the pGSK-3β/GSK-3β ratio.

Conclusions These results provide novel evidence for cardioprotection through acute PKC{delta} inhibition in aged rat heart following I/R. Our results also suggest, for the first time, a key role for mitochondrial GSK-3β as a cellular basis for the protection associated with PKC{delta} inhibition with ageing.

KEYWORDS Senescence; Myocardial infarction; GSK-3β; Protein kinase B (Akt473); Apoptosis

Time for primary review 22 days


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