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.

译文

雌激素替代在降低绝经后女性心血管死亡率方面无效的发现,对女性心脏保护的年龄依赖性逆转的潜在机制知之甚少,并且变得复杂。尽管已经在幼小动物中发现了几种保护信号,包括PKC和Akt,但这些信号如何受到年龄,雌激素缺乏和缺血再灌注 (I/R) 的影响仍然未知。确定年龄和雌激素缺乏对I/R损伤和下游pkc-akt信号传导的独立和综合影响。使用Langendorff灌注 (31分钟整体缺血) 对完整卵巢或卵巢切除术 (Ovx) 的成年和老年雌性F344大鼠 (n = 12/年龄) 进行I/R。通过蛋白质印迹分析评估I/R后胞质 (s),核 (n),线粒体 (m) PKC (δ,ε) 水平的变化以及总Akt和mGSK-3beta磷酸化的变化。衰老增加了卵巢完整女性的梗死面积50% (P <0.05),而左室功能恢复或雌二醇水平没有差异。与成年大鼠相比,Ovx在老年大鼠中更大程度地降低了功能恢复 (P <0.05)。在老年人 (与成人相比) 中,m-和nPKC(-δ,-ε) 水平明显降低,而mgsk3β 水平升高 (P <0.05)。Ovx导致更高水平的sPKC(-δ,-ε) 独立于年龄 (P <0.05)。在卵巢完整的老年女性中,I/R将p-Akt(Ser473) 水平降低了57%,并将mGSK-3beta积累增加了1.77倍 (P <0.05)。这些数据首次表明,仅雌激素不能保护老年女性心肌免受I/R损伤,并且PKC,Akt和GSK-3beta信号传导的年龄和雌激素依赖性改变可能导致缺血耐受性丧失。

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