Role of Immunometabolism in Myocardial Infarction Outcomes in Metabolic Syndrome

肥胖和高血压(即代谢综合征)在经历心肌梗死(MI)的患者中非常普遍。除了增加发生心肌梗死的风险外，这些危险因素还会促进心肌梗死后不利的左心室重构，从而增加心肌梗死后心力衰竭的发展。然而，肥胖和高血压相互作用促进心肌梗死后异常结局的机制还不是很清楚。一种可能的机制是通过炎症，其中单核/巨噬细胞发挥关键作用。虽然巨噬细胞对正常伤口愈合和炎症消退至关重要，但它们也可以促进愈合不足，并在慢性病状态下加剧炎症。心肌梗死后，单核细胞迅速侵入坏死的左室，分化为心肌梗死前炎症巨噬细胞，以产生炎症反应，然后随着创面愈合的进展，分化或分化为M2抗炎巨噬细胞，以化解炎症。免疫细胞代谢(免疫代谢)已被认为是决定极化的关键因素；然而，MI后免疫代谢的作用尚未被研究。心脏代谢受到心脏慢性应激源的损害，如肥胖和高血压，这些新陈代谢的变化有助于疾病的进展。因此，本研究的主要目的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，以及控制巨噬细胞代谢是否可以改善代谢综合征的心肌梗死后结局。为了实现这一目标，小鼠将被长期喂食高脂肪和高果糖(即西方)的饮食来诱导肥胖，并将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心肌梗死。巨噬细胞的极化和代谢表型将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。在目标2中，小鼠将被给予2-脱氧葡萄糖以扰乱葡萄糖代谢，并被给予亚硝酸钠以增强线粒体脂肪酸氧化。巨噬细胞表型与心肌梗死后的预后有关，如存活、心功能和心脏重塑。

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.