Cardioprotective role of Humanin in aging

摘要 衰老是心血管疾病的一个危险因素。冠状动脉疾病是导致死亡的主要原因， 世界范围内的发病率。代谢变化和氧化应激发生在心肌中的阶段， 缺血和再灌注引起心肌损伤，并在发展和 心肌损伤和心力衰竭（HF）的进展。Humanin（HN）是一种新型小肽， 线粒体，已被证明在许多年龄相关疾病中表现出强的细胞保护作用， 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。 糖尿病我们的小组已经证明，HN的施用导致梗死面积的减小， 在心肌缺血-再灌注（MI-R）损伤的小鼠模型中保存心脏功能。 此外，我们在本资助申请中提供的初步数据显示，HN管理导致：1） 在衰老啮齿动物和临床相关的MI-R猪模型中MI-R损伤后梗死面积减小; 2） 改善心脏功能，如通过患有心肌梗死的老年小鼠的舒张末期容积降低所证明的 缺血诱导的心力衰竭; 3）增加过氧化物酶体脂肪酸氧化，抑制线粒体 原代心肌细胞和心脏裂解物中的脂肪酸氧化; 4）降低ROS和5）提高存活率 缺氧和氧化应激后心肌细胞的死亡率。基于这些数据，我们假设HN 治疗将通过其独特的能力改善MI-R损伤或MI诱导的心力衰竭（HF）的心脏功能 诱导心肌细胞的代谢适应，改善过氧化物酶体功能并降低ROS， 从而限制急性心肌细胞死亡，并防止发展为HF。在这份资助申请中，我们 将描述HN在衰老中MI-R损伤和MI诱导的HF的鼠模型中的心脏保护功效 阐明HN对心肌保护作用的机制。以探索性 子目标，我们将评估患有缺血后心力衰竭的人类受试者的心脏和循环中的HN水平。 这些实验的结果可能对治疗心血管疾病产生巨大影响。 HN可能为患者提供急需的治疗选择，以保护心肌免受缺血和 再灌注损伤，并防止进展为HF。

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.