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Cardiovascular Aging

Local delivery of PKC-activating peptide mimics ischemic preconditioning in aged hearts through GSK-3 but not F₁-ATPase inactivation

¹Intercollege Program in Physiology and ²Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania; and ³Department of Medicine, University of Wisconsin, Madison, Wisconsin

Submitted 31 March 2007 ; accepted in final form 2 August 2007

In adult heart, selective PKC activation limits ischemia (I)-reperfusion (R) damage and mimics the protection associated with ischemic preconditioning. We sought to determine whether local delivery of PKC activator peptide -receptor for activated C-kinase (-RACK) is sufficient to produce a similarly protected phenotype in aged hearts. Langendorff-perfused hearts isolated from adult (5 mo; n = 9) and aged (24 mo; n = 9) male Fisher 344 rats were perfused with -RACK conjugated to Tat (500 nM) or Tat only (500 nM) for 10 min before global 31-min ischemia. Western blotting was used to measure mitochondrial targeting of PKC, PKC, phospho (p)-GSK-3 (Ser⁹) and GSK-3 in hearts snap-frozen during I. Recovery of left ventricular developed pressure was significantly improved by -RACK (P < 0.01) and infarct size reduced in 24-mo rats vs. age-matched controls (60% vs. 34%; P < 0.01). Mitochondrial PKC levels were 30% greater during I with -RACK in aged vs. control rats (P < 0.01). Interestingly, mitochondrial GSK-3 levels were threefold greater in aged vs. adult rats during I, and -RACK prevented this increase (P < 0.01). Mitochondrial p-GSK-3 levels were also greater in aged rats after -RACK (P < 0.01), and subsequent inhibition of GSK-3 with SB-216763 (3 µM) before I/R elicited protection similar to that of -RACK (n = 3/group). Mitochondrial proteomic analysis further identified group differences in the F₁-ATPase -subunit, and coimmunoprecipitation studies revealed a novel interaction with PKC. F₁-ATPase-PKC association was affected by -RACK in adult but not aged rats. Our results provide evidence, for the first time, for PKC-mediated protection in aged rat heart after I/R and suggest a central role for mitochondrial GSK-3 but not F₁-ATPase as a potential target of PKC to limit I/R damage with aging.

ischemia-reperfusion injury; proteomics; mitochondria; senescence