Ovariectomy Reduces Ischemic Tolerance in Aged but not Adult Rat Myocardium

Abstract

Background Epidemiological data indicates that hormone replacement therapy is ineffective at reducing cardiovascular morbidity and mortality in aged females. Although several protective signals have been identified in young animals including PKCε and Akt, the role these signals play in the recovery from ischemia-reperfusion (I/R) in aged females is poorly understood. Purpose To determine the independent and combined effects of age and estrogen deficiency on I/R injury and downstream PKCε − Akt signaling. Methods Adult (Y) and aged (O) female F344 rats (n=12/age) with ovaries intact or ovariectomy (Ovx) were subjected to I/R using Langendorff perfusion (31 min global I). Triphenyl tetrazolium chloride staining was used to assess infarct size, and recovery function determined as left ventricular developed pressure (LVDP). Changes in mitochondrial (m) PKCε levels, Akt and GSK3β phosphorylation following I/R were assessed by western blotting. Results Infarct size was 50% greater in O vs Y (p<0.05), while no differences in LVDP or estradiol levels were observed. With OVX, reduced LVDP recovery was noted in O (80%, p<0.05) but not Y; infarct size was also greater in O+OVX vs O. I/R decreased mPKCε levels by 50% in both Y and O (p<0.05), and significantly decreased phosphorylation of Akt and GSK-3β in O (relative to total Akt and GSK-3β levels). Summary These data suggest that age-dependent reductions in ischemic tolerance are not exclusively due to plasma estradiol deficiency and that age- and estrogen-dependent alterations in protective PKCε and Akt signaling may contribute to loss of ischemic tolerance.