Exercise, Antioxidants, and I-R Injury

描述(申请人提供)：运动训练促进对缺血再灌注(I-R)损伤的心脏保护。具体地说，耐力运动训练减少了I-R诱导的蛋白水解酶(即钙蛋白酶)的激活、氧化损伤和心肌梗死。负责这种运动介导的心脏保护的机制仍不清楚，也是本提案的重点。解释运动保护作用的潜在机制包括改善侧支循环，提高心脏热休克蛋白，以及增强心肌抗氧化能力。根据已发表的工作和我们实验室的初步实验，我们假设，改善心肌抗氧化剂可以最大限度地减少I-R诱导的钙蛋白酶激活和氧化损伤，并且对于运动诱导的心肌梗死保护至关重要。具体地说，我们假设运动诱导的对I-R损伤的保护严重依赖于运动诱导的心脏中锰超氧化物歧化酶(MnSOD)活性和谷胱甘肽(GSH)水平的增加。这一假设将在两个具体目标上得到检验。首先，我们将确定运动诱导的对I-R诱导的钙蛋白酶激活和氧化损伤的保护是否依赖于心肌MnSOD活性和GSH水平的增加。其次，我们将确定运动诱导的心肌MnSOD活性和心肌GSH水平的增加是否是预防I-R诱导的心肌梗死所必需的。我们将结合药理学和分子生物学方法(如MnSOD的反义寡核苷酸)，独立地阻止运动诱导的心肌MnSOD和GSH的合成。然后，我们将使用心肌I-R的体内模型来确定运动诱导的心肌MnSOD和GSH的增加是否在保护心肌免受I-R对心脏的损害方面是必不可少的。这些研究将提高我们对运动诱导的I-R损伤保护机制的理解，并将对有心肌I-R损伤风险的患者的管理具有重要意义。

DESCRIPTION (provided by applicant): Exercise training promotes cardioprotection against ischemia-reperfusion (I-R) injury. Specifically, endurance exercise training reduces I-R-induced protease (i.e. calpain) activation, oxidative injury, and myocardial infarction. The mechanism responsible for this exercise-mediated cardioprotection remains unclear and is the focus of this proposal. Potential mechanisms to explain the protective effect of exercise include improved collateral circulation, elevation of cardiac heat shock proteins, and increased myocardial antioxidant capacity. Based on published work and preliminary experiments in our laboratory, we postulate that improvements in myocardial antioxidants minimize I-R-induced calpain activation and oxidative injury and are essential for exercise-induced protection against infarction. Specifically, we hypothesize that the exercise-induced protection against an I-R insult is critically dependent on a training-induced increase in both manganese superoxide dismutase (MnSOD) activity and glutathione (GSH) levels in the heart. This hypothesis will be tested in two specific aims. First, we will determine if the exercise-induced protection against I-R-induced calpain activation and oxidative injury is dependent upon an increase in myocardial MnSOD activity and GSH levels. Secondly, we will ascertain if the exercise-induced increase in both myocardial MnSOD activity and myocardial GSH levels are essential for protection against I-R-induced myocardial infarction. Using both pharmacological and molecular approaches (e.g. antisense oligodeoxyribonucleotides to MnSOD), we will independently prevent the exercise-induced synthesis of myocardial MnSOD and GSH. We will then use an in vivo model of myocardial I-R to determine if exercise-induced increases in both myocardial MnSOD and GSH are essential in protecting against the damaging effects of I-R on the heart. These studies will improve our understanding of the mechanisms responsible for exercise-induced protection against I-R damage and will have important implications for management of patients at risk for myocardial I-R injury.