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.
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