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.