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Am J Physiol Heart Circ Physiol (August 3, 2007). doi:10.1152/ajpheart.00403.2007
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Submitted on March 31, 2007
Accepted on August 2, 2007

Local Delivery of PKC{epsilon}-Activating Peptide Mimics Ischemic Preconditioning in Aged Hearts Through GSK3{beta} but not F1ATPase Inactivation

Donna H. Korzick1*, John C Kostyak2, James Craig Hunter2, and Kurt W. Saupe3

1 Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States; Intercollege Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania, United States
2 Intercollege Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania, United States
3 Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States

* To whom correspondence should be addressed. E-mail: dhk102{at}psu.edu.

In adult heart, selective PKC{epsilon} activation limits ischemia/reperfusion (I/R) damage and mimics the protection associated with ischemic preconditioning. We sought to determine whether local delivery of an PKC{epsilon}-activator peptide ({psi}{epsilon}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 either {psi}{epsilon}RACK conjugated to Tat (500 nM) or Tat-only (500 nM) for 10 min prior to global 31 min ischemia. Western blotting was used to measure mitochondrial targeting of PKC{epsilon}, PKC{delta}, p-GSK-3{beta} (ser9) and GSK-3{beta} in hearts snap frozen during I. Recovery of LV developed pressure was significantly improved by {psi}{epsilon}RACK (p<0.01) and infarct size reduced in 24 mo vs age-matched controls (60% vs 34%; p<0.01). Mitochondrial PKC{epsilon} levels were 30% greater during I with {psi}{epsilon}RACK in aged vs controls (p<0.01). Interestingly, mitochondrial GSK-3{beta} levels were 3-fold greater in aged vs adult during I, and {psi}{epsilon}RACK prevented this increase. Mitochondrial p-GSK-3{beta} levels were also greater in aged following {psi}{epsilon}RACK (p<0.01), and subsequent inhibition of GSK-3{beta} with SB 216763 (3 µM) prior to I/R elicited protection similar to that observed for {psi}{epsilon}RACK (n=3/group). Mitochondrial proteomic analysis further identified group differences in the F1-ATPase-{beta} subunit, and coimmunoprecipitation studies revealed a novel interaction with PKC{epsilon}. F1-ATPase-PKC{epsilon} association was affected by &#968;&#949;RACK in adult but not aged. Our results provide evidence, for the first time, for PKC{epsilon}-mediated protection in aged rat heart following I/R. Our results also suggest a central role for mitochondrial GSK-3{beta} but not the F1ATPase as a potential target of PKC{epsilon} to limit I/R damage with aging.




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