Przyklenk Karin, Li Guohu, Simkhovich Boris Z, Kloner Robert A
Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
J Appl Physiol (1985). 2003 Dec;95(6):2563-9. doi: 10.1152/japplphysiol.00404.2003. Epub 2003 Aug 8.
Data obtained from adult cohorts have implicated activation/translocation of protein kinase C (PKC)-epsilon 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-epsilon as a mediator of infarct size reduction with PC in old vs. adult rabbits. In protocol 1, we assessed the effect of PKC-epsilon translocation inhibitor peptide (PKC-epsilon-TIP) and the pan-PKC inhibitor chelerythrine on infarct size reduction with PC in adult and approximately 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. In protocol 2, we obtained insight (by Western immunoblotting) into the subcellular redistribution of PKC-epsilon 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-epsilon-TIP and chelerythrine. However, in old rabbits, 1). PC-induced cardioprotection was maintained despite inhibitor treatment and 2). brief PC ischemia was not associated with activation/translocation of PKC-epsilon. Thus the mechanisms responsible for PC are age related in the rabbit heart, with no apparent, requisite role of PKC-epsilon in aging animals.
从成年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）减少心肌梗死面积的重要细胞介质。然而，细胞信号传导中与年龄相关的变化可能会混淆从成年人得出的机制性见解向老年人群的推断，而老年人群无疑是心脏保护最相关的特定亚组。因此，我们的目的是研究PKC-ε作为PC减少梗死面积的介质在老年兔与成年兔中的作用。在方案1中，我们评估了PKC-ε易位抑制剂肽（PKC-ε-TIP）和泛PKC抑制剂白屈菜红碱对成年兔和大约4岁兔（先前已证明该群体表现出心血管衰老的明确特征）中PC减少梗死面积的影响。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，梗死面积（通过四氮唑染色描绘）作为主要终点。在方案2中，我们（通过蛋白质免疫印迹法）深入了解了成年兔和老年兔中PKC-ε在5分钟PC刺激下的亚细胞重新分布。在成年兔中，PKC-ε-TIP和白屈菜红碱均消除了PC引起的梗死面积减少。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然存在；2）。短暂的PC缺血与PKC-ε的激活/易位无关。因此，兔心脏中负责PC的机制与年龄有关，PKC-ε在衰老动物中没有明显的必要作用。
