The role of ATP citrate lyase in cardiac macrophage-mediated inflammation aftermyocardial infarction

Myocardial infarction (MI) is the number one killer in the Western world. Especially, war veterans are highly prone to post-MI morbidity and mortality. Recent breakthrough technologies in the treatment of MI patients have decreased in-hospital mortality. However, long-term morbidity and mortality due to complications, such as reinfarction and heart failure, still persist. Several studies and the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have shown that inflammation plays a crucial role in these complications. Yet, the exact mechanisms of exaggerated inflammation after MI are not clearly understood. Different pathways of cellular metabolism, such as fatty acid oxidation and oxidative phosphorylation, can modulate inflammatory cell function. In the proposed grant application, we will decipher the role of the fatty acid synthesis pathway in innate inflammation. ATP citrate lyase (ACLY), an enzyme in this pathway, is well known for its role in histone acetylation and transcription factor activation. However, if increased availability of this enzyme in macrophages after MI augments cardiac inflammation and fibrosis by modifying the epigenome is not known. We will investigate the role of ACLY in altering the epigenome of cardiac macrophages, leading to exaggerated inflammation, excessive myocardial fibrosis, and deteriorated cardiac function after MI.