Role of Immunometabolism in Myocardial Infarction Outcomes in Metabolic Syndrome

免疫代谢在代谢综合征心肌梗死结局中的作用

基本信息

批准号：
10269071
负责人：
Alan J Mouton
金额：
$ 24.07万
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：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269071
关键词：
Abdomen Affect Anti-Inflammatory Agents Aortic coarctation Cardiac Cell Respiration Cellular Metabolic Process Chronic Chronic Disease Coronary artery Deoxyglucose Disease Progression Fatty acid glycerol esters Fluorescence-Activated Cell Sorting Fructose Goals Heart Heart failure Hypertension Immune Impairment Inflammation Inflammatory Inflammatory Response Invaded Left Ventricular Remodeling Ligation Link Metabolic Diseases Metabolic syndrome Metabolism Mitochondria Mus Myocardial Infarction Necrosis Obesity Operative Surgical Procedures Outcome Patients Phenotype Play Research Risk Risk Factors Role Sodium Nitrite cardiogenesis experience fatty acid oxidation glucose metabolism healing heart function heart metabolism improved macrophage metabolic phenotype monocyte stressor transcriptome sequencing western diet wound healing

项目摘要

Obesity and hypertension (i.e. metabolic syndrome) are highly prevalent in patients who experience myocardial infarction (MI). In addition to increasing the risk of developing MI, these risk factors also promote adverse left ventricular remodeling after MI and thus increase the development of heart failure after MI. However, the mechanisms by which obesity and hypertension interact to promote aberrant post-MI outcomes are not well understood. One possible mechanism is through inflammation, in which monocytes/macrophages play key roles. While macrophages are critical for normal wound healing and resolution of inflammation, they can also promote inadequate healing and exacerbate inflammation during chronic disease states. Following MI, monocytes quickly invade the necrotic LV and differentiate into MI pro-inflammatory macrophages to generate an inflammatory response, then as wound healing progresses differentiate or “polarize” into M2 anti-inflammatory macrophages to resolve inflammation. Immune cell metabolism (immunometabolism) has been identified as a key factor dictating polarization; however, the role of immunometabolism following MI has not been investigated. Cardiac metabolism is impaired by chronic stressors on the heart, such as obesity and hypertension, and these changes in metabolism contribute to disease progression. Thus, the main goal of this study is to identify how obesity and hypertension interact to affect cardiac macrophage polarization and metabolism after MI, and whether manipulating macrophage metabolism can improve post-MI outcomes in metabolic syndrome. To accomplish this goal, mice will be fed a chronic high fat and high fructose (i.e. Western) diet to induce obesity, and hypertension will be surgically induced by abdominal aortic coarctation. Mice will then be given MI by permanent coronary artery ligation. Macrophage polarization and metabolic phenotypes will be assessed by fluorescence activated cell sorting (FACS), RNA-Seq, and glycolytic and Oxidative metabolism. In Aim 2, mice will be administered 2-deoxyglucose to perturb glucose metabolism and sodium nitrite to enhance mitochondrial fatty acid oxidation. Macrophage phenotypes will be linked to post-MI outcomes such as survival, cardiac function, and cardiac remodeling.

肥胖和高血压（即代谢综合征）在心肌梗死 (MI) 患者中非常普遍，除了增加发生 MI 的风险外，这些危险因素还会促进 MI 后不良的左心室重构，从而增加心力衰竭的发生。然而，肥胖和高血压相互作用导致心肌梗死后异常结果的机制尚不清楚，其中单核细胞/巨噬细胞发挥着关键作用，而巨噬细胞则至关重要。对于伤口的正常愈合和炎症的消退，它们还可以在慢性疾病状态下促进愈合不充分和炎症加剧，单核细胞迅速侵入坏死的左心室并分化为 MI 促炎巨噬细胞，产生炎症反应，然后促进伤口愈合。进展分化或“极化”为 M2 抗炎巨噬细胞以解决炎症免疫细胞代谢（免疫代谢）已被确定为决定极化的关键因素；然而，MI 后免疫代谢的作用。心脏代谢受到慢性压力源（例如肥胖和高血压）的损害，而这些代谢变化会导致疾病进展，因此，本研究的主要目标是确定肥胖和高血压如何相互作用产生影响。心肌梗死后心脏巨噬细胞的极化和代谢，以及操纵巨噬细胞代谢是否可以改善代谢综合征的心肌梗死后的结果为了实现这一目标，将给小鼠喂食长期高脂肪和高果糖（即西方）饮食以诱导肥胖和高血压。将然后通过永久性冠状动脉结扎手术诱导小鼠发生 MI，并通过荧光激活细胞分选 (FACS)、RNA-Seq 以及糖酵解和氧化代谢来评估代谢表型。小鼠将被给予 2-脱氧葡萄糖以扰乱葡萄糖代谢，并给予亚硝酸钠以增强线粒体脂肪酸氧化。心肌梗死后的结果，如生存、心功能和心脏重塑。