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Rapid Estrogen Receptor- Activation Improves Ischemic Tolerance in Aged Female Rats through a Novel Protein Kinase C-Dependent Mechanism

Intercollege Program in Physiology (J.L.N., A.M.S., N.J.T., D.H.K.) and The Department of Kinesiology (T.S.L., D.H.K.), The Pennsylvania State University, University Park, Pennsylvania 16802

Address all correspondence and requests for reprints to: Donna H. Korzick, Ph.D., 106 Noll Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802. E-mail: dhk102{at}psu.edu.

The effects of estrogen deficiency on the loss of cardioprotection with advancing age are complex and poorly understood. A major focus of the current study was to uncover a cardioprotective role for rapid, nongenomic estrogen receptor (ER) signaling in the aged female myocardium. We hypothesized that selective ER activation in aged females would reduce infarct size in part, through reversal of age-associated reductions in mitochondrial protein kinase C (PKC). Hearts isolated from adult (6 month old) and aged (23–24 months old) female F344 rats with ovaries removed (n = 20 per group) were subjected to ischemia/reperfusion (47 min global ischemia). Rats were injected sc with the ER agonist propylpyrazole triol (PPT) or vehicle 45 min before heart isolation (5 µg/kg). Infarct size was greatest in aged vs. adult ovariectomized rats, significantly reduced by PPT, and the protection reversed by prior administration of the ER inhibitor ICI 182,780 (3 mg/kg). Increased ER particulate targeting occurred after PPT in conjunction with reversal of age-related reductions in nuclear PKC, mitochondrial PKC and pAkt (P < 0.05). PPT also increased mRNA levels for the PKC anchoring protein, receptor for activated C kinase2 (RACK2; P < 0.05). Our data suggest, for the first time, that selective ER activation reduces ischemic injury in the aged, estrogen-deficient heart through a mechanism involving nongenomic redistribution of ER and PKC activation. A novel feed-forward transcriptional mechanism to potentially enhance PKC-RACK2 interactions was also observed. Collectively, our findings may provide key insight into developing targeted therapeutic interventions in postmenopausal women to reduce ischemia/reperfusion injury, including selective ER mimetics.