Anti-Inflammatory Roles and Macrophage Metabolism of Lactate and Ketones during Myocardial Infarction

心肌梗死期间乳酸和酮的抗炎作用和巨噬细胞代谢

• 批准号: 10736579
• 负责人: Alan J Mouton
• 金额: $ 60.98万
• 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: 2023-08-11 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736579
• 关键词: 4D Imaging; Acetoacetates; Address; Adult; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Attenuated; Automobile Driving; Carbohydrates; Cardiac; Cardiovascular Diseases; Cicatrix; Coronary artery; Coupled; Data; Development; Diabetes Mellitus; Diabetic mouse; Diagnostic; Dose; Echocardiography; Endothelium; Enzymes; Epidemic; Epigenetic Process; Fatty Acids; Fibroblasts; Fibrosis; Flow Cytometry; Gene Expression; Genes; Genus Hippocampus; Glucose; Glycolysis; Granulation Tissue; Heart; Heart Injuries; Heart failure; High Fat Diet; Histones; Hyperglycemia; Impairment; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Interleukin-1 beta; Intervention; Ischemia; Ketone Bodies; Ketones; Knockout Mice; Left; Life Style; Ligation; Macrophage; Measures; Mediating; Mediator; Metabolic; Metabolism; Mitochondria; Modification; Mus; Muscle Cells; Myocardial Infarction; Myocardial dysfunction; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Phosphorylation; Oxygen; Patients; Persons; Phase; Phenotype; Play; Production; Proliferating; Property; Proteins; Resolution; Risk; Risk Factors; Role; SLC2A1 gene; Sodium Lactate; Sorting; Source; Starvation; Streptozocin; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transferase; United States; angiogenesis; beta-Hydroxybutyrate; cardiogenesis; cardioprotection; chromatin immunoprecipitation; clinically relevant; comorbidity; diabetic patient; feeding; glucose metabolism; glucose uptake; healing; heart function; improved; in vivo; ketogenic diet; metabolomics; mortality; mouse model; necrotic tissue; new therapeutic target; novel; novel strategies; novel therapeutic intervention; oxidation; pharmacologic; prevent; preventive intervention; stable isotope; success; succinyl-coenzyme A; therapeutic target; translational model; ultrasound; wound healing

PROJECT SUMMARY/ABSTRACT Approximately 1 million people in the United States suffer a myocardial infarction (MI) each year, leading to progressive cardiac dysfunction and development of heart failure (HF) in ~25% of surviving patients. Diabetes mellitus is a major risk factor for MI, and patients with diabetes suffer from higher mortality rates and increased risk of developing HF. Due to the limited success of current therapies in preventing adverse cardiac remodeling after MI, novel therapeutic targets are needed to effectively promote adequate healing and limit tissue damage, especially in diabetic patients. Excessive macrophage-mediated inflammation is a key mechanism leading to adverse cardiac remodeling after MI, and patients with diabetes display exacerbated and persistent post-MI inflammatory responses. A key mechanism by which macrophages polarize between the pro-inflammatory “M1” and anti-inflammatory/pro-reparative “M2” subsets is via metabolic reprogramming characterized by phenotypic switches between glycolytic metabolism, which promotes M1 polarization, and mitochondrial oxidative phosphorylation (OXPHOS), which promotes M2 polarization. Using Seahorse metabolic flux analysis, I have found that during the early inflammatory phase (day 1 and 3 after MI in mice), infarct macrophages become glycolytic, whereas during the healing phase (day 7), macrophages revert to glucose oxidation and OXPHOS. In addition to glucose, macrophages can metabolize “alternative” fuels, including lactate and ketone bodies, which promote an M2 phenotype. However, the role of lactate and ketone body metabolism by macrophages during MI is unknown, and whether administration or endogenous production of these compounds can promote M2 macrophage polarization during MI is also not known. My preliminary data indicate that expression of genes related to lactate (Mct1, Ldhb) and ketone (Oxct1) metabolism are upregulated in macrophage during the wound healing phase of MI. Further preliminary data indicates that in vivo administration of lactate or ketones, or feeding a ketogenic diet attenuates the macrophage immunometabolic phenotype after MI. This indicates that metabolism of these substrates may underlie M2 polarization and cardiac healing after MI. Thus, the hypothesis for this proposal is that elevated endogenous production or exogenous administration of lactate and ketones will improve cardiac remodeling and reduces cardiac injury after MI via improved macrophage metabolism and polarization. I also propose that diabetes exacerbates MI injury via impaired macrophage lactate and ketone metabolism. To address these hypotheses, I will use clinically relevant mouse models of MI and diabetes mellitus, and macrophage-specific genetically modified mice, coupled with state-of- the-art techniques for measuring cardiac function (high resolution ultrasound echocardiography and 4D imaging), live cellular metabolism, macrophage isolation by immunomagnetic sorting, and flow cytometry. These studies will provide new mechanisms of lactate and ketone-mediated cardioprotection, and novel strategies for targeting macrophage metabolism following cardiac injury.

项目总结/摘要 美国每年约有100万人患有心肌梗死（MI），导致 约25%的存活患者发生进行性心功能不全和心力衰竭（HF）。糖尿病 糖尿病是MI的主要危险因素，糖尿病患者的死亡率更高， 发展HF的风险。由于目前的治疗方法在预防不良心脏重塑方面的成功有限， 在MI后，需要新的治疗靶点来有效地促进充分愈合并限制组织损伤， 尤其是在糖尿病患者中。过度的巨噬细胞介导的炎症是导致 心肌梗死后不良心脏重塑，糖尿病患者心肌梗死后表现出恶化和持续 炎症反应。巨噬细胞在促炎症“M1”之间极化的关键机制 抗炎/促修复“M2”亚群通过代谢重编程，其特征在于表型 在促进M1极化的糖酵解代谢和线粒体氧化代谢之间切换 磷酸化（OXPHOS），其促进M2极化。利用海马代谢通量分析，我得到了 发现在早期炎症阶段（小鼠心肌梗死后第1天和第3天）， 在愈合阶段（第7天），巨噬细胞恢复葡萄糖氧化和OXPHOS。在 除了葡萄糖，巨噬细胞还可以代谢“替代”燃料，包括乳酸盐和酮体， 促进M2表型。然而，乳酸和酮体代谢的巨噬细胞的作用， 尚不清楚MI，以及这些化合物的给药或内源性产生是否可促进M2 MI期间巨噬细胞极化也是未知的。我的初步数据表明基因的表达 与乳酸（Mct 1，Ldhb）和酮（Oxct 1）代谢相关的蛋白质在创伤期间在巨噬细胞中上调 MI的愈合阶段。进一步的初步数据表明，在体内给予乳酸盐或酮，或喂养， 生酮饮食减弱MI后巨噬细胞免疫代谢表型。这表明 这些底物的代谢可能是MI后M2极化和心脏愈合的基础。因此，假设 因为这一建议是乳酸的内源性产生或外源性给药的增加， 酮将通过改善巨噬细胞功能，改善心肌重塑并减少MI后的心脏损伤。 代谢和极化。我还认为糖尿病通过损害心肌细胞的功能， 巨噬细胞乳酸和酮代谢。为了解决这些假设，我将使用临床相关的小鼠 心肌梗死和糖尿病模型，巨噬细胞特异性基因修饰小鼠，加上国家的， 用于测量心脏功能的现有技术（高分辨率超声心动图和4D成像）， 活细胞代谢、通过免疫磁性分选的巨噬细胞分离和流式细胞术。这些研究 将提供新的机制，乳酸和酮介导的心脏保护，和新的战略， 心脏损伤后的巨噬细胞代谢。