Project Summary Abstract Coronary heart disease is responsible for over half a million deaths annually. According to extensive post- mortem human correlation studies, atherosclerotic plaque stability, rather than lesion size, is the best determinant of adverse thrombotic events and associated myocardial infarction or stroke. Plaque stability is improved by the presence of an extracellular matrix-rich fibrous cap, thought to be largely produced by smooth muscle-derived cells. Currently, there are no therapies that directly improve plaque stability as a means to decrease incidence of adverse cardiac events. Current cardiovascular disease patients, both symptomatic and asymptomatic, need novel, interventional, therapies to improve plaque stability as a way to prevent future heart attack and stroke. There is a critical need to identify mechanisms that promote beneficial changes in smooth muscle cell phenotype, specifically the abilities of investing in the fibrous cap and producing extracellular matrix components to stabilize plaques. Preliminary in vitro studies suggest that smooth muscle cells are absolutely dependent on certain energy metabolism, or bioenergetic, pathways for extracellular matrix production. Specifically, we found that cultured smooth muscle cell extracellular matrix production requires functioning aerobic glycolysis – the conversion of pyruvate to lactate thought to be an inefficient energy production mechanism. We found that aerobic glycolysis in cultured smooth muscle cells can be inhibited through pharmacological suppression of lactate dehydrogenase or enhanced through pharmacological suppression of pyruvate dehydrogenase, which results in inhibited or enhanced extracellular matrix gene expression, respectively. This proposal seeks to test the hypothesis that bioenergetic manipulation of smooth muscle cells in vivo can augment extracellular matrix production, fibrous cap thickness, and thus plaque stability. Briefly, this proposal aims to pharmacologically and genetically inhibit lactate dehydrogenase or pyruvate dehydrogenase as a means of smooth muscle cell collagen production inhibition or augmentation, respectively, after the development of atherosclerotic lesions in smooth muscle cell-lineage tracing mice. This study will test the feasibility of manipulating smooth muscle cellular metabolism as an interventional therapy for atherosclerosis.