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.

项目概要/摘要 每年有超过 150 万美国人患有心肌梗塞 (MI)，其中约 25% 的患者 出现严重的心脏功能障碍，包括充血性心力衰竭 (HF)，其 5 年死亡率很高 率~50%。目前心肌梗死后的治疗在减轻心功能不全和减慢心功能方面取得的成功有限。 心力衰竭进展。因此，迫切需要新颖、更有效的疗法来保护心脏、改善心脏功能。 它的功能，并减缓/停止心脏功能障碍的进展。我们最近证明了激活 脑瘦素-黑皮质素系统通路极大改善心肌细胞能量代谢和收缩力， 保留心脏功能，并防止左前心结扎引起的心肌梗死后心力衰竭的进展 冠状动脉降支。我们观察到，脑室内 (ICV) 注射瘦素 4 周，剂量为 低剂量不会改变血液瘦素浓度、恢复射血分数、心输出量、左心室 (LV) 肌肉拉伤和左心房/主动脉直径比几乎一直回到正常基线值，并且 初步数据表明，心脏功能的其他指标，例如 +dP/dtmax 和运动能力 也明显改善。我们还观察到黑皮质素 4 不存在这些心脏保护作用 受体（MC4R）缺陷的大鼠，使用合成激动剂注入大脑 MC4R 激活 脑室以类似的方式保护心脏免受心肌梗死后进行性心功能障碍的影响 与瘦素治疗相比。我们的初步数据还表明 CNS 瘦素-MC4R 通路的激活 增加 Sirtuin-3 (SIRT3) 表达、线粒体生物合成和底物氧化（即葡萄糖和脂肪 酸氧化），并改善左心室非梗塞区域（包括以下区域）的心肌细胞收缩力 有风险但仍然可行。该提案的中心假设是大脑黑皮质素系统的激活 改善心脏功能并防止心肌梗死后心力衰竭的进展，增强心肌功能 线粒体生物合成和 SIRT3 水平，增强底物氧化并提高能量 心脏健康部分的产生和心肌细胞收缩力。我们还建议这些 黑皮质素系统对心脏的有益作用需要 PVN 中的 MC4R 激活和/或 DMV/NTS/IML，以及可穿过血脑屏障的 MC4R 激动剂（例如 setmelanotide）并可 即使在肥胖的情况下，全身给药也能有效地提供心脏保护作用。 我们将使用最先进的慢性体内方案和高分辨率超声技术进行成像 基因工程动物的心脏功能（包括4D应变超声心动图成像技术） 模型与离体和体外制剂相结合，用于详细测量心肌功能， 形态、能量代谢和收缩性来检验我们的假设。这项研究的结果可以 导致 MI 和 HF 的新颖且更有效的治疗方法，并将为 MC4R 提供新的靶点 目前用于治疗人类罕见遗传性肥胖症的激动剂。