PMID:17008461

Citation	Hunter, JC, Kostyak, JC, Novotny, JL, Simpson, AM and Korzick, DH (2007) Estrogen deficiency decreases ischemic tolerance in the aged rat heart: Roles of PKCdelta, PKCepsilon, Akt, and GSK3beta. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292:R800-9
Abstract	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 (delta, epsilon) levels, and changes in total Akt and mGSK-3beta 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 m- and nPKC(-delta, -epsilon) were markedly decreased, whereas mGSK3beta levels were increased (P < 0.05). Ovx led to greater levels of sPKC(-delta, -epsilon) independent of age (P < 0.05). I/R reduced p-Akt(Ser473) levels by 57% and increased mGSK-3beta 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-3beta signaling may contribute to loss of ischemic tolerance.
Links	PubMed Online version:10.1152/ajpregu.00374.2006
Keywords	Aging/pathology; Animals; Blotting, Western; Body Weight/drug effects; Coloring Agents; Coronary Circulation/physiology; Cytochromes c/metabolism; Estrogens/deficiency; Female; Glycogen Synthase Kinase 3/physiology; Male; Myocardial Ischemia/etiology; Myocardial Ischemia/physiopathology; Myocardial Reperfusion Injury/metabolism; Oncogene Protein v-akt/physiology; Ovariectomy; Protein Kinase C-delta/physiology; Protein Kinase C-epsilon/physiology; Rats; Rats, Inbred F344; Tetrazolium Salts
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:KPCD	involved_in	GO:0007568: aging	ECO:0000270: expression pattern evidence used in manual assertion		P		Seeded From UniProt	complete
RAT:KPCD	part_of	GO:0005739: mitochondrion	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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