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,PKC
, Akt, and GSK3
1 Physiology, Penn State University, University Park, Pennsylvania, United States
2 Physiology and Kinesiology, Penn State University, State College, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: dhk102{at}psu.edu.
The mechanisms underlying the age-dependent reversal of female cardioprotection are poorly understood, and complicated by findings that estrogen replacement is ineffective at reducing CV mortality in post-menopausal 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 I). Changes in cytosolic (s), nuclear (n), mitochondrial (m) PKC (
, 
) levels, and changes in total Akt and mGSK-3
phosphorylation following I/R were assessed by western blotting. Senescence increased infarct size 50% in ovary-intact females (p<0.05), while no differences in LV functional recovery or estradiol levels were observed. Ovariectomy reduced functional recovery to a greater extent in aged compared with adult rats (p<0.05). In aged (vs adult), levels of m and n PKC(-, -) were markedly decreased, whereas mGSK3 levels were increased (p<0.05). Ovx led to greater levels of cytosolic PKC(-, -) independent of age (p<0.05). I/R reduced p-Akt(Ser473) 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 age- and estrogen-dependent alterations in PKC, Akt, and GSK-3 signaling may contribute to loss of ischemic tolerance.
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