Cardioprotective role of Humanin in aging

护脑素在衰老过程中的心脏保护作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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，冠状动脉疾病是导致死亡的主要原因。全世界的发病率。代谢变化和氧化应激发生在心肌中。缺血和再灌注会导致心肌损伤，并在发育和发育中发挥关键作用。心肌损伤和心力衰竭（HF）的进展，护脑素（HN）是一种由人产生的新型小肽。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 型氧化应激我们的研究小组已经证明，给予 HN 可以减少梗塞面积并减少糖尿病的发生。心肌缺血再灌注（MI-R）损伤小鼠模型中心脏功能的保存。此外，我们在本次赠款提交中提供的初步数据显示，HN 管理导致：1) 老年啮齿动物和临床相关的 MI-R 猪模型中 MI-R 损伤后梗塞面积减少 2) 患有心肌病的老年小鼠的舒张末期容积减少表明心脏功能得到改善缺血引起的心力衰竭；3) 过氧化物酶体脂肪酸氧化增加，并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，5) 提高存活率；根据这些数据，我们捕获了 HN。治疗将通过其独特的能力改善 MI-R 损伤或 MI 诱发的心力衰竭 (HF) 中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减少活性氧，限制急性心肌细胞死亡，并防止进展为心力衰竭。在这项拨款申请中，我们将描述 HN 在 MI-R 损伤和衰老过程中 MI 诱发的 HF 小鼠模型中的心脏保护功效并阐明 HN 对心肌的心脏保护作用的机制。子目标是，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心肌损伤。再灌注损伤，并防止进展为心力衰竭。