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 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 (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 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 KID1-1 (p<0.05), increasing the pGSK-3beta/GSK-3beta ratio. CONCLUSIONS: These results provide novel evidence for cardioprotection through acute PKCdelta inhibition in aged rat heart following I/R. Our results also suggest, for the first time, a key role for mitochondrial GSK-3beta as a cellular basis for the protection associated with PKCdelta inhibition with ageing.
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 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 (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 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 KID1-1 (p<0.05), increasing the pGSK-3beta/GSK-3beta ratio. CONCLUSIONS: These results provide novel evidence for cardioprotection through acute PKCdelta inhibition in aged rat heart following I/R. Our results also suggest, for the first time, a key role for mitochondrial GSK-3beta as a cellular basis for the protection associated with PKCdelta inhibition with ageing.
Authors: Magdalena Juhaszova; Dmitry B Zorov; Yael Yaniv; H Bradley Nuss; Su Wang; Steven J Sollott Journal: Circ Res Date: 2009-06-05 Impact factor: 17.367
Authors: Lihua Ao; Yufeng Zhai; Chunhua Jin; Joseph C Cleveland; David A Fullerton; Xianzhong Meng Journal: Mol Med Date: 2016-12-19 Impact factor: 6.354
Authors: Jason N Peart; Salvatore Pepe; Melissa E Reichelt; Nikkie Beckett; Louise See Hoe; Victoria Ozberk; Ingrid R Niesman; Hemal H Patel; John P Headrick Journal: Exp Gerontol Date: 2013-12-04 Impact factor: 4.032
Authors: Mark J Mondrinos; Linda C Knight; Paul A Kennedy; Jichuan Wu; Matthew Kauffman; Sandy T Baker; Marla R Wolfson; Laurie E Kilpatrick Journal: J Pharmacol Exp Ther Date: 2015-08-04 Impact factor: 4.030