Mechanisms of myocardial ischemic preconditioning are age related: PKC-epsilon does not play a requisite role in old rabbits.
Mechanisms of myocardial ischemic preconditioning are age related: PKC-epsilon does not play a requisite role in old rabbits.
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心肌缺血预处理的机制与年龄有关：PKC-ε 在老年兔子中不发挥必要的作用。
DOI：
10.1152/japplphysiol.00404.2003
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Kloner,RobertA
中科院分区：
文献类型：
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作者：
Przyklenk,Karin;Li,Guohu;Simkhovich,BorisZ;Kloner,RobertA
从成人队列获得的数据表明蛋白激酶 C (PKC)-ε 的激活/易位是缺血预处理 (PC) 减少心肌梗塞面积的重要细胞介质。然而，细胞信号传导中与年龄相关的改变可能会混淆从成年人到老龄化人群的机制见解的外推，而老龄化人群中心脏保护无疑是最相关的特定子集。因此，我们的目的是研究 PKC-ϵ 作为 PC 在老年兔和成年兔中减少梗塞面积的中介者的作用。在方案 1 中，我们评估了 PKC-ϵ 易位抑制肽 (PKC-ϵ-TIP) 和泛 PKC 抑制剂白屈菜红碱对 PC 减少成年和 4 岁兔子梗塞面积的影响，这些兔子此前已被证明表现出心血管衰老的明确标志。兔子接受 5 分钟的 PC 缺血或匹配的对照期，然后进行 30 分钟的冠状动脉闭塞和 3 小时的再灌注，以梗死面积（通过四唑染色描绘）作为主要终点。在方案 2 中，我们（通过蛋白质免疫印迹）了解了成年兔和老年兔响应 5 分钟 PC 刺激时 PKC-ϵ 的亚细胞重新分布。在成人中，PC 减少梗塞面积的作用被 PKC-ε-TIP 和白屈菜红碱消除。然而，在老年兔中，1）尽管进行了抑制剂治疗，PC 诱导的心脏保护作用仍得以维持，2）短暂的 PC 缺血与 PKC-ε 的激活/易位无关。因此，导致 PC 的机制与兔子心脏中的年龄相关，而 PKC-ϵ 在衰老动物中没有明显的必要作用。
Data obtained from adult cohorts have implicated activation/translocation of protein kinase C (PKC)-ϵ as an important cellular mediator of myocardial infarct size reduction with ischemic preconditioning (PC). Age-related alterations in cellular signaling may, however, confound the extrapolation of mechanistic insight derived from adults to the aging population, the specific subset in which cardioprotection is undoubtedly most relevant. Accordingly, our aim was to investigate the role of PKC-ϵ as a mediator of infarct size reduction with PC in old vs. adult rabbits. Inprotocol 1, we assessed the effect of PKC-ϵ translocation inhibitor peptide (PKC-ϵ-TIP) and thepan-PKC inhibitor chelerythrine on infarct size reduction with PC in adult and ∼4-yr-old rabbits, a population previously shown to exhibit definitive hallmarks of cardiovascular aging. Rabbits received 5 min of PC ischemia or a matched control period followed by 30 min of coronary artery occlusion and 3 h of reperfusion, with infarct size (delineated by tetrazolium staining) serving as the primary endpoint. Inprotocol 2, we obtained insight (by Western immunoblotting) into the subcellular redistribution of PKC-ϵ in response to the 5-min PC stimulus in adult and old rabbits. In adults, infarct size reduction with PC was abrogated by both PKC-ϵ-TIP and chelerythrine. However, in old rabbits,1) PC-induced cardioprotection was maintained despite inhibitor treatment and2) brief PC ischemia was not associated with activation/translocation of PKC-ϵ. Thus the mechanisms responsible for PC are age related in the rabbit heart, with no apparent, requisite role of PKC-ϵ in aging animals.