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Acute PKCδ Inhibition Limits Ischemia‐Reperfusion Injury in the Aged Rat Heart: Role of GSK‐3β
Author(s) -
Korzick Donna Hope,
Kostyak John Creigh,
Hunter James Craig
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1155-d
Subject(s) - cardioprotection , medicine , ischemia , dna laddering , apoptosis , protein kinase c , cardiology , basal (medicine) , reperfusion injury , endocrinology , programmed cell death , signal transduction , biology , biochemistry , insulin , dna fragmentation
Age is a leading risk factor for the development of ischemic heart disease and failure. However, the efficacy of cardioprotective strategies designed to rescue the aged myocardium remain controversial. We have previously demonstrated increased levels of basal cardiac PKCδ with aging, a well‐known mediator of apoptotic cell death following ischemia and reperfusion (I/R) in adult hearts. In the current study, we sought to determine the contribution of PKCδ signaling mechanisms to age‐related reductions in ischemic tolerance using local delivery of a novel PKCδ‐inhibitory peptide (KID1‐1). Contractile responses were assessed in hearts isolated from adult (4 mo; n=36) and aged (24 mo; n=40) male Fisher 344 rats treated with either KID1‐1 (500 nM) or vehicle (500 nM) upon reperfusion following 31 min global ischemia. Recovery of LV developed pressure was significantly improved by KID1‐1 and associated with smaller infarct size in 24 mo vs age‐matched controls (p<0.005). We also observed significant reductions in DNA laddering, cytochrome C and caspase 3 levels in aged hearts treated with KID1‐1. Interestingly, KID1‐1 attenuated mitochondrial and nuclear PKCδ levels during reperfusion in aged vs age‐matched controls (p<0.01). Further, increases in mitochondrial p‐GSK‐3β levels were hastened in aged vs adult hearts following KID1‐1 (p<0.05), increasing the p‐GSK‐3β/GSK‐3β ratio. These results provide novel evidence for cardioprotection through acute PKCδ 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 PKCδ inhibition with aging.