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

• 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
• 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

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）在发生心肌梗死（MI）的患者中非常普遍。除了增加发生MI的风险外，这些风险因素还促进MI后不良的左心室重构，从而增加MI后心力衰竭的发生。然而，肥胖和高血压相互作用促进心肌梗死后异常结果的机制尚不清楚。一种可能的机制是通过炎症，其中单核细胞/巨噬细胞发挥关键作用。虽然巨噬细胞对于正常伤口愈合和炎症的解决至关重要，但它们也可以促进慢性疾病状态期间的愈合不足并加剧炎症。MI后，单核细胞迅速侵入坏死LV并分化为MI促炎巨噬细胞以产生炎症反应，然后随着伤口愈合的进展分化或“分化”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，尚未研究MI后免疫代谢的作用。心脏代谢受到心脏慢性应激源的损害，如肥胖和高血压，这些代谢变化有助于疾病进展。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，影响心肌梗死后的心脏巨噬细胞极化和代谢，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结果。为了实现这一目标，将给小鼠喂食慢性高脂肪和高果糖（即西式）饮食以诱导肥胖，并通过腹主动脉缩窄手术诱导高血压。然后通过永久性冠状动脉结扎给予小鼠MI。将通过荧光激活细胞分选（FACS）、RNA-Seq以及糖酵解和氧化代谢评估巨噬细胞极化和代谢表型。在目标2中，将向小鼠施用2-脱氧葡萄糖以干扰葡萄糖代谢，并施用亚硝酸钠以增强线粒体脂肪酸氧化。巨噬细胞表型将与MI后结局（如生存率、心脏功能和心脏重塑）相关。