Endothelial Cell Respiration in Atherosclerotic Plaque Erosion Heart disease is the number one cause of death in the United States and worldwide. Coronary artery disease, the most common type of heart disease, is the root cause of acute coronary syndromes, and accounts for 7.4 million deaths per year globally. Nearly all these events stem from atherosclerotic plaque rupture or erosion. While knowledge of plaque rupture has improved in recent decades, comparatively little is known about plaque erosion and its underlying molecular mechanisms – despite recent recognition that it may cause from 25 to 60% of acute coronary syndromes and is increasing in incidence. Plaque erosion is defined by loss of endothelial cells (ECs) leading to thrombosis in the absence of plaque rupture. The pathophysiology of erosion is largely unexplored; the few studies on this topic focus on extrinsic factors that induce EC loss. However, most erosions are clinically silent, which suggests that eroded regions usually heal well enough to prevent an acute coronary syndrome. Notably, the molecular mechanisms underlying repair in plaque erosion are unknown. Our research proposal will study EC intrinsic factors that may change the likelihood that ECs will be lost to death or desquamation, or will contribute to repair, in particular, looking at mitochondrial mechanisms that are unexplored in this setting. During angiogenesis, mitochondrial respiration and metabolism support EC proliferation and migration by mechanisms other than ATP production. We hypothesize that EC respiration is required to support endothelial homeostasis and promote repair during re-endothelialization and plaque erosion. Using tools of molecular and cellular biology and mouse genetics, we will evaluate: a) whether EC respiration promotes cellular activities relevant for endothelial repair of eroded plaques, and unveil underlying molecular mechanisms, b) whether EC respiration supports arterial homeostasis or promotes re- endothelialization after arterial denudation, and c) whether EC respiration oposses plaque erosion or supports re-endothelialization of eroded plaques. Our studies will also incorporate an innovative method to study the endothelium in three-dimensions, and include the evaluation of human atherosclerotic plaques. This research project will bring a new perspective to the nascent field of plaque erosion pathophysiology, focused on mitochondria and cell metabolism, which may open new avenues to prevent or treat acute coronary syndrome.