Cardioprotective role of Humanin in aging

护脑素在衰老过程中的心脏保护作用

• 批准号: 10642873
• 负责人: Partha Dutta
• 金额: $ 47.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642873
• 关键词: Acute; Acute myocardial infarction; Adolescent; Affect; Age; Age Years; Aging; Alzheimer' s Disease; Apoptosis; Apoptotic; Applications Grants; Area; Atherosclerosis; Attenuated; Biological Markers; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Death; Cerebral Ischemia; Cessation of life; Chronic; Circulation; Clinical; Complement; Coronary Arteriosclerosis; Coronary heart disease; Cytoprotection; Data; Development; Disease; Dose; Elderly; Enzymes; Exhibits; Family; Family suidae; Fatty Acids; Frequencies; Gender; Genetic; Grant; Health; Heart; Heart Transplantation; Heart failure; Human; Hypoxia; Impaired cognition; Incidence; Infarction; Injections; Injury; Ischemia; Knock-out; Knowledge; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Metabolism; Miniature Swine; Mitochondria; Modality; Modeling; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial tissue; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Patients; Peptides; Phase; Play; Prevention; Publishing; Reperfusion Injury; Reperfusion Therapy; Risk; Risk Factors; Rodent; Role; Stroke; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Harvesting; Tissues; Viral; acyl-CoA oxidase; age related; aged; cardioprotection; cardiovascular risk factor; catalase; clinically relevant; coronary fibrosis; experimental study; fatty acid oxidation; heart function; heart preservation; human subject; humanin; improved; in vivo; insight; ischemic injury; male; member; middle age; mortality; mortality risk; mouse model; myocardial damage; myocardial injury; neuroprotection; novel; percutaneous coronary intervention; peroxisome; porcine model; preclinical study; prevent; protective factors

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.

抽象的 衰老是心血管疾病的危险因素。冠状动脉疾病是死亡的主要原因， 全球发病率。在心肌中发生的代谢转移和氧化应激。 缺血和再灌注会导致心肌损伤，并在发展中起关键作用 心肌损伤和心力衰竭（HF）的进展。 Humanin（HN），一种新颖的小胡椒 线粒体已被证明在许多与年龄有关的疾病中表现出强大的细胞保护作用 氧化应激，包括阿尔茨海默氏病，动脉粥样硬化，心肌和脑缺血以及2型 糖尿病。我们的小组表明，HN给药会导致梗塞大小的减小和 在心肌缺血再灌注（MI-R）损伤的小鼠模型中，心脏功能保留。 此外，我们在本赠款提交中提供的我们的初步数据表明，HN管理结果：1） MI-R的老化啮齿动物和与临床相关的MI-R型衰老啮齿动物损伤后的梗塞尺寸减小； 2） 心肌的老鼠的末端舒张压减少证明了心脏功能的改善 缺血引起的心力衰竭； 3）增加过氧化物体脂肪酸氧化并抑制线粒体 原发性心肌细胞和心脏裂解物中的脂肪酸氧化； 4）减少ROS，5）提高生存率 缺氧和氧化应激后的心肌细胞。基于这些数据，我们假设HN 治疗将通过其独特的能力来改善MI-R损伤或MI诱发心力衰竭（HF）的心脏功能 为了诱导心肌细胞的代谢适应，改善过氧化物体功能并减少ROS， 从而限制急性心肌细胞死亡，并防止向HF发展。在此赠款申请中，我们 将描述HN在MI-R损伤和MI诱导的HF衰老的鼠模型中的心脏保护效率 并阐明了HN对心肌的心脏保护作用的机制。在探索性中 sub Aim，我们将评估心脏衰竭后人类受试者的心脏和循环水平。 这些实验的结果可能会在治疗心血管疾病中产生巨大影响。 HN可能为患者提供急需的治疗选择，以保护心肌免受缺血性和 再灌注损伤，并防止进展到HF。