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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要美国约有100万人每年遭受心肌梗塞（MI）约25％的尚存患者的进行性心脏功能障碍和心力衰竭（HF）的发育（HF）。糖尿病 Mellitus是MI的主要危险因素，糖尿病患者死亡率较高，并增加发展HF的风险。由于当前疗法在防止不良心脏重塑方面取得的成功有限 MI之后，需要新的热目标以有效促进足够的愈合并限制组织损伤，过度巨噬细胞介导的炎症是导致的关键机制 MI后心脏重塑不良，糖尿病患者表现出恶化和持续的MI 炎症反应。巨噬细胞在促炎的“ M1”之间极化的关键机制抗炎/促侵占的“ M2”子集是通过表型为特征的代谢重编程在促进M1极化和线粒体氧化的糖酵解代谢之间切换磷酸化（OXPHOS），促进M2极化。使用海马代谢通量分析，我有发现在炎症阶段早期（小鼠MI后的第1和第3天），梗塞巨噬细胞变成糖酵解，而在愈合阶段（第7天），巨噬细胞恢复为葡萄糖氧化和Oxphos。在除葡萄糖外，巨噬细胞还可以代谢“替代”燃料，包括鞋底和酮体，这些燃料，这些燃料促进M2表型。但是，巨噬细胞在 MI是未知的，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不知道。我的初步数据表明基因的表达在伤口期间，巨噬细胞更新了与鞋底（MCT1，LDHB）和酮（OXCT1）代谢相关的 MI的愈合阶段。进一步的初步数据表明，体内给药鞋底或酮或喂养 MI后，生酮饮食会减轻巨噬细胞免疫代谢表型。这表明这些底物的代谢可能是M2极化和MI后心脏愈合的基础。那是假设对于此提案，是内源性产生或牙层的外源性施用酮通过改善巨噬细胞后改善心脏重塑并减少心脏损伤代谢和极化。我还建议糖尿病因受损而加剧MI损伤巨噬细胞乳酸和酮代谢。为了解决这些假设，我将使用临床上相关的鼠标 MI和糖尿病的模型，以及巨噬细胞特异性的遗传改性小鼠，并与最新测量心脏功能的艺术技术（高分辨率超声超声心动图和4D成像），活细胞代谢，通过免疫磁分选和流式细胞仪进行巨噬细胞分离。这些研究将提供新的鞋底和酮介导的心脏保护的机制，以及针对性的新型策略心脏损伤后的巨噬细胞代谢。