Cardioprotective role of Humanin in aging

摘要 衰老是心血管疾病的一个危险因素。冠状动脉疾病是主要的死亡原因和 世界范围内的发病率。心肌中的代谢变化和氧化应激 缺血和再灌流可引起心肌损伤，在心肌损伤的发生和发展中起着关键作用。 心肌损伤和心力衰竭的进展。人蛋白(HN)，一种新的由人产生的小肽 线粒体，已被证明在许多与年龄相关的疾病中表现出强大的细胞保护作用， 氧化应激包括阿尔茨海默病、动脉粥样硬化、心肌和脑缺血以及2型 糖尿病。我们的小组已经证明，服用HN会导致梗塞面积的减少和 心肌缺血再灌注(MI-R)损伤小鼠模型的心功能保护。 此外，我们在这份拨款申请中提供的初步数据显示，HN管理的结果是：1) 老年啮齿动物MI-R损伤后脑梗塞范围缩小及临床相关的MI-R猪模型；2) 心肌梗死老年小鼠舒张末容量减少可明显改善心功能 缺血诱导的心力衰竭；3)过氧化体脂肪酸氧化增加，线粒体受到抑制 原代心肌细胞和心脏裂解物中的脂肪酸氧化；4)降低ROS，5)提高存活率 低氧和氧化应激后对心肌细胞的影响。根据这些数据，我们假设HN 治疗将通过其独特的能力改善MI-R损伤或MI所致心力衰竭(HF)的心功能 诱导心肌细胞代谢适应，改善过氧化体功能，降低ROS， 从而限制急性心肌细胞死亡，防止进展为心衰。在这项拨款申请中，我们 将阐明HN在MI-R损伤和MI致衰老心衰小鼠模型中的心脏保护作用 并阐明了HN对心肌保护作用的机制。在探索性的 亚目标，我们将评估人类缺血后心力衰竭患者心脏和循环中的HN水平。 这些实验的结果可能会对治疗心血管疾病产生巨大影响。 HN可能为患者提供一种急需的治疗选择，以保护心肌免受缺血和 再灌注损伤，并防止进展为心衰。

Abstract Aging is a risk factor for cardiovascular diseases. Coronary artery disease is the leading cause of death and morbidity world-wide. Metabolic shifts and oxidative stress that occur in the myocardium during the phases of ischemia as well as reperfusion cause myocardial injury and play a pivotal role in the development and progression of myocardial damage and heart failure (HF). Humanin (HN), a novel small peptide generated by mitochondria, has been shown to exhibit strong cytoprotection in many age-related diseases with increased oxidative stress including Alzheimer’s disease, atherosclerosis, myocardial and cerebral ischemia, and type 2 diabetes. Our group has demonstrated that administration of HN results in a decrease in infarct size and preservation of cardiac function in a mouse model of myocardial ischemia-reperfusion (MI-R) injury. Additionally, our preliminary data presented in this grant submission shows that HN administration results in: 1) infarct size reduction following MI-R injury in aging rodent and clinically-relevant porcine models of MI-R; 2) improved cardiac function as evidenced by decreased end diastolic volume in old mice with myocardial ischemia-induced heart failure; 3) increased peroxisomal fatty acid oxidation, and inhibition of mitochondrial fatty acid oxidation in primary cardiomyocytes and heart lysates; 4) decreases ROS and 5) improved survival of cardiomyocytes following hypoxia and oxidative stress. Based on these data, we hypothesize that HN treatment will improve cardiac function in MI-R injury or MI induced heart failure (HF) through its unique ability to induce metabolic adaptations in cardiac myocytes, improve peroxisomal function and decrease ROS, thereby limiting acute myocardial cell death, and preventing the progression to HF. In this grant application, we will delineate the cardioprotective efficacy of HN in murine models of MI-R injury and MI induced HF in aging and elucidate the mechanisms that underlie HN’s cardioprotective effects on the myocardium. In an exploratory sub aim, we will assess HN levels in heart and circulation in human subjects with post-ischemia cardiac failure. Results from these experiments may potentially have a tremendous impact in treating cardiovascular diseases. HN may provide a much-needed therapeutic option for patients to protect the myocardium from ischemic and reperfusion injuries, and prevent the progression to HF.