Anti-Inflammatory Roles and Macrophage Metabolism of Lactate and Ketones during Myocardial Infarction - 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.
