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.

项目概要/摘要 美国每年约有 100 万人患有心肌梗塞 (MI)，导致 约 25% 的幸存糖尿病患者出现进行性心功能障碍和心力衰竭 (HF)。 糖尿病是心肌梗死的主要危险因素，糖尿病患者死亡率较高，且死亡率增加 由于目前的治疗方法在预防不良心脏重塑方面效果有限。 心肌梗死后，需要新的治疗靶点来有效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糖尿病的关键机制。 心肌梗死后出现不良心脏重塑，糖尿病患者在心肌梗死后表现出恶化和持续的症状 炎症反应是巨噬细胞在促炎症“M1”之间极化的关键机制。 抗炎/促修复“M2”子集是通过以表型为特征的代谢重编程实现的 在促进 M1 极化的糖酵解代谢和线粒体氧化之间切换 使用 Seahorse 代谢通量分析，我得到了促进 M2 极化的磷酸化 (OXPHOS)。 发现在早期炎症阶段（小鼠心肌梗死后第 1 天和第 3 天），梗塞巨噬细胞变得 糖酵解，而在愈合阶段（第 7 天），巨噬细胞恢复葡萄糖氧化和 OXPHOS。 除了葡萄糖之外，巨噬细胞还可以代谢“替代”燃料，包括乳酸和酮体， 促进 M2 表型然而，巨噬细胞在乳酸和酮体代谢中的作用。 MI 尚不清楚，这些化合物的给药或内源性产生是否可以促进 M2 MI 期间的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（Mct1、Ldhb）和酮（Oxct1）代谢相关的巨噬细胞在伤口期间上调 进一步的初步数据表明，体内施用乳酸或酮，或喂养。 生酮饮食会减弱心肌梗死后的巨噬细胞免疫代谢表型。 这些底物的代谢可能是 MI 后 M2 极化和心脏愈合的基础。 该建议的目的是增加乳酸的内源性生产或外源性施用 酮将通过改善巨噬细胞改善心脏重塑并减少心肌梗死后的心脏损伤 我还认为糖尿病会通过受损来加重心肌梗死损伤。 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，以及巨噬细胞特异性转基因小鼠，加上状态- 用于测量心脏功能的最先进技术（高分辨率超声心动图和 4D 成像）， 活细胞代谢、通过免疫磁分选分离巨噬细胞和流式细胞术。 将提供乳酸和酮介导的心脏保护的新机制，以及靶向的新策略 心脏损伤后巨噬细胞的代谢。