CALL FOR PAPERS Sex Diferences in Renal and Cardiovascular Function: Physiology and Pathophysiology Estrogen deficiency decreases ischemic tolerance in the aged rat heart: roles of PKC , PKC , Akt, and GSK3

Hunter JC, Kostyak JC, Novotny JL, Simpson AM, Korzick DH. Estrogen deficiency decreases ischemic tolerance in the aged rat heart: roles of PKC , PKC , Akt, and GSK3 . Am J Physiol Regul Integr Comp Physiol 292: R800–R809, 2007. First published September 28, 2006; doi:10.1152/ajpregu.00374.2006.—The mechanisms underlying the age-dependent reversal of female cardioprotection are poorly understood and complicated by findings that estrogen replacement is ineffective at reducing cardiovascular mortality in postmenopausal women. Although several protective signals have been identified in young animals, including PKC and Akt, how these signals are affected by age, estrogen deficiency, and ischemia-reperfusion (I/R) remains unknown. To determine the independent and combined effects of age and estrogen deficiency on I/R injury and downstream PKC-Akt signaling, adult and aged female F344 rats (n 12/age) with ovaries intact or ovariectomy (Ovx) were subjected to I/R using Langendorff perfusion (31-min global-ischemia). Changes in cytosolic (s), nuclear (n), mitochondrial (m) PKC ( , ) levels, and changes in total Akt and mGSK-3 phosphorylation after I/R were assessed by Western blot analysis. Senescence increased infarct size 50% in ovary-intact females (P 0.05), whereas no differences in LV functional recovery or estradiol levels were observed. Ovx reduced functional recovery to a greater extent in aged compared with adult rats (P 0.05). In aged (vs. adult), levels of mand nPKC(, ) were markedly decreased, whereas mGSK3 levels were increased (P 0.05). Ovx led to greater levels of sPKC(, ) independent of age (P 0.05). I/R reduced p-Akt(Ser) levels by 57% and increased mGSK-3 accumulation 1.77-fold (P 0.05) in aged, ovary-intact females. These data suggest, for the first time, that estrogen alone cannot protect the aged female myocardium from I/R damage and that ageand estrogen-dependent alterations in PKC, Akt, and GSK-3 signaling may contribute to loss of ischemic tolerance.