PRECONDITIONING THE AGED HEART: EFFICACY AND MECHANISMS

短暂的非致死性心肌缺血可以保护心脏或“预处理”心脏，并极大地限制由后期持续的冠状动脉闭塞引起的梗死面积。这种自相矛盾的缺血诱导的梗死面积减少的证据在迄今为止评价的所有物种和模型中都有记录，尽管负责这种保护的机制仍然没有得到很好的解决，但越来越多的数据表明G蛋白偶联信号转导（具体地，蛋白激酶C的激活和/或肌醇1，4，5-三磷酸释放的改变），在短暂的预处理刺激期间开始，作为这种现象的重要细胞介质。尽管在过去的十年中，人们对缺血预处理进行了大量的研究，但值得注意的是，到目前为止，预处理对心脏的保护作用几乎完全是用幼年或成年动物进行的。一个明显的问题是短暂的缺血是否能有效地保护老年或衰老的心脏免受随后的梗死。 然而，这个问题几乎是未经探索的，在目前发表的研究中，已经获得了不一致的结果。 因此，本试验性建议的主要目的是明确确定预处理是否能减少老年心脏的梗死面积。 实验将使用局部缺血的离体缓冲液灌注的兔心脏模型进行，通过四唑染色描绘梗死面积。 其次，我们将开始评估和比较G蛋白介导的信号转导启动短暂的预处理缺血在老年人与成人心肌，再次在兔心脏，肌醇三磷酸含量和亚细胞蛋白激酶C活性定量使用市售的测定。人们希望从缺血预处理研究中获得的知识最终可能导致设计新的治疗策略来保护人类心脏免受梗死。 在这方面，衰老的心脏是否适合于预处理诱导的保护的问题是至关重要的，因为老年人群正是心肌梗死最普遍的临床人群，因此，心脏保护是最相关的。

Brief episodes of nonlethal myocardial ischemia protect or "precondition" the heart and profoundly limit infarct size caused by a later sustained period of coronary artery occlusion. Evidence of this paradoxical, ischemia-induced reduction of infarct size has been documented in all species and models evaluated to date and, although the mechanisms responsible for this protection remain poorly resolved, an ever-increasing body of data has implicated G-protein-coupled signal transduction (specifically, activation of protein kinase C and/or alterations in inositol 1,4,5-triphosphate release), initiated during the brief preconditioning stimulus, as important cellular mediators of this phenomenon. Despite the intensive effort devoted to ischemic preconditioning during the past decade, it is perhaps remarkable that cardioprotection with preconditioning has, to this point, almost exclusively been investigated using juvenile or adult animals. An obvious question is whether brief antecedent ischemia effectively protects the aged or senescent heart against subsequent infarction. However, this issue is virtually unexplored and, among the handful of currently published studies, discrepant results have been obtained. Thus, the primary aim of this pilot proposal is to definitively determine whether infarct size reduction with preconditioning is manifest in the aged heart. Experiments will be conducted using the isolated buffer- perfused rabbit heart model of regional ischemia, with infarct size delineated by tetrazolium staining. Second, we will begin to evaluate and compare G-protein-mediated signal transduction initiated by brief preconditioning ischemia in aged versus adult myocardium, again in rabbit heart, with inositol trisphosphate content and subcellular protein kinase C activities quantified using commercially available assays. It is hoped that knowledge obtained from the study of ischemic preconditioning may ultimately lead to the design of novel therapeutic strategies to protect the human heart against infarction. In this regard, the question of whether the senescent heart is amenable to preconditioning-induced protection is of fundamental importance, as the aged cohort is precisely the clinical population in which myocardial infarction is most prevalent and, thus, cardioprotection is most relevant.