Saturday, December 21, 2024
12/21/2024
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.
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