Acute PKCdelta inhibition limits ischaemia-reperfusion injury in the aged XXXX heart: role of @entity9096 .

@entity9096 @entity1188 @entity24878 @entity299 @entity35 @entity4124
OBJECTIVE: Age is a leading risk factor for the development of @entity299 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 Cdelta (PKCdelta) 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 PKCdelta signaling mechanisms to reperfusion injury in the aged heart using local delivery of a novel PKCdelta inhibitory peptide ( @entity24878 -1). METHODS: Contractile responses were assessed in hearts isolated from adult (4 months, n=38) and aged (24 months, n=45) male Fisher 344 @entity35 treated with either @entity24878 -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 @entity24878 -1 and associated with smaller @entity1188 size in 24 months vs. age-matched controls (p<0.005). We also observed significant reductions in DNA laddering and cytochrome c and @entity4124 levels in aged hearts treated with @entity24878 -1. Interestingly, @entity24878 -1 attenuated mitochondrial and nuclear PKCdelta levels during reperfusion in aged vs. age-matched controls (p<0.01). Further, increases in mitochondrial phosphorylated glycogen synthase kinase-3beta (pGSK-3beta) levels were hastened in aged and adult hearts following @entity24878 -1 (p<0.05), increasing the pGSK-3beta/ @entity9096 ratio. CONCLUSIONS: These results provide novel evidence for cardioprotection through acute PKCdelta inhibition in aged @entity35 heart following I/R. Our results also suggest, for the first time, a key role for mitochondrial @entity9096 as a cellular basis for the protection associated with PKCdelta inhibition with ageing.
