Cardiac protective mechanisms of melanocortin system activation

黑皮质素系统激活的心脏保护机制

• 批准号: 10585732
• 负责人: Alexandre Alves da Silva
• 金额: $ 58.56万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-09 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585732
• 关键词: Agonist; American; Animal Model; Animals; Anterior Descending Coronary Artery; Aorta; Area; Back; Biogenesis; Blood; Blood - brain barrier anatomy; Brain; Brain Stem; Bypass; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Central Nervous System; Cerebral Ventricles; Chronic; Congestive Heart Failure; Data; Diameter; Disease Progression; Dose; EFRAC; Echocardiography; Energy Metabolism; Genetic; Genetic Engineering; Glucose; Healthcare; Heart; Heart failure; Human; Hypothalamic structure; Imaging Techniques; Imaging technology; In Vitro; Infusion procedures; Knock-out; Lateral; Left; Left atrial structure; Left ventricular structure; Leptin; Leptin resistance; Ligation; Measurement; Measures; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolic stress; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Mus; Muscle function; Muscle strain; Myocardial Infarction; Myocardial dysfunction; Myocardium; Obesity; Outcome Study; Pathway interactions; Patients; Peripheral; Preparation; Production; Protocols documentation; Rattus; Receptor Activation; Resistance; Resolution; Risk; Risk Factors; Sirtuins; System; Testing; Thinness; United States; blood-brain barrier crossing; cardioprotection; care burden; cholinergic neuron; dorsal motor nucleus; effective therapy; exercise capacity; fatty acid oxidation; heart function; heart preservation; improved; in vivo; innovation; melanotan-II; mortality; novel; novel therapeutic intervention; obese patients; obesity genetics; oxidation; paraventricular nucleus; prevent; protective effect; success; therapeutically effective; ultrasound

PROJECT SUMMARY/ABSTRACT Over 1.5 million Americans suffer from myocardial infarction (MI) each year, and about 25% of these patients develop severe cardiac dysfunction including congestive heart failure (HF), which has a high 5-year mortality rate of ~50%. Current therapies following MI have limited success in attenuating cardiac dysfunction and slowing HF progression. Thus, there is a critical need for novel, more effective therapies that protect the heart, improve its function, and slow/halt progression of cardiac dysfunction. We recently demonstrated that activation of the brain leptin-melanocortin system pathway greatly improves cardiomyocyte energy metabolism and contractility, preserves cardiac function, and prevents progression of HF following MI induced by ligation of the left anterior descending coronary artery. We observed that intracerebroventricular (ICV) infusion of leptin for 4 weeks, at a low dose that did not alter blood leptin concentration, restored ejection fraction, cardiac output, left ventricle (LV) muscle strain and left atrium/aorta diameter ratio almost all the way back to normal baseline values, and preliminary data suggest that other measures of cardiac function such as +dP/dtmax and exercise capacity were also markedly improved. We also observed that these cardiac protective effects are absent in melanocortin 4 receptor (MC4R) deficient rats and that activation of brain MC4R using synthetic agonists infused into the cerebral ventricles protected the heart against progressive cardiac dysfunction after MI in a similar fashion compared to leptin treatment. Our preliminary data also indicate that activation of the CNS leptin-MC4R pathway increases sirtuin-3 (SIRT3) expression, mitochondrial biogenesis and substrate oxidation (i.e., glucose and fatty acid oxidation), and improves cardiomyocyte contractility in non-infarcted regions of the LV, including areas at risk but still viable. The central hypothesis of this proposal is that activation of the brain melanocortin system improves cardiac function and prevents progression of HF after MI, increases myocardium mitochondrial biogenesis and SIRT3 levels, enhances substrate oxidation, and improves energy production and cardiomyocyte contractility in healthy portions of the heart. We also propose that these beneficial effects of the melanocortin system on the heart require MC4R activation in PVN and/or DMV/NTS/IML, and that MC4R agonists that cross the blood-brain barrier (e.g. setmelanotide) and can be administered systemically will be effective to provide cardioprotective even in the setting of obesity. We will use state-of-the-art chronic in vivo protocols with high-resolution ultrasound techniques for imaging cardiac function (including 4D-strain echocardiographic imaging technology) in genetically engineered animal models combined with ex vivo and in vitro preparations for detailed measurements of cardiac muscle function, morphology, energy metabolism and contractility to test our hypotheses. The outcomes from this study could lead to novel and more effective therapeutic approaches for MI and HF, and will provide a new target for MC4R agonists which are currently being used to treat rare forms of genetic obesity in humans.

项目总结/文摘