The role of signaling adaptor protein epsin in atherosclerosis

PROJECT SUMMARY/ABSTRACT
Atherosclerosis is the leading cause of life-threatening coronary heart disease, ischemic stroke, and peripheral
arterial disease in the United States. Notably, dyslipidemia remains a major risk factor despite effective lipid-
lowering therapies and prevention programs. This is, in part, due to overwhelming arterial inflammation that
drives the transition from a stable to vulnerable and rupture-prone atheroma. The lack of effective therapies to
lower circulating cholesterol while forcefully curbing arterial inflammation during atheroma progression
presents an opportunity to develop innovative, new medicines for this devastating disease. Understanding the
causative molecular mechanisms responsible for dyslipidemia and arterial inflammation should provide for the
rapid development of more potent therapeutic approaches. Our long-term goal is to uncover molecular
mechanisms underlying the pathophysiology and unearth fresh potential therapeutic targets. Much of our
earlier research has centered on examining the role of epsin endocytic adaptor proteins in endothelial cells and
macrophages to regulate progression of atherogenesis. We have demonstrated that epsins 1 and 2 are
upregulated in atherosclerotic plaques in mouse models of atherosclerosis and human atherosclerotic lesions.
Consequently, deletion of epsins in the endothelium and macrophages resulted in marked attenuation of
atherogenesis. Mechanistically, we showed that epsins escalate arterial inflammation by expressing adhesion
molecules, enhancing monocyte recruitment, and hindering efferocytosis. More recently, we created a liver-
specific deficiency of epsins in an atherosclerotic mouse model and found that atherogenesis was greatly
inhibited and accompanied with diminished blood cholesterol levels and triglyceride levels. Therefore, targeting
epsins, their binding partners, and downstream targets represents an attractive therapeutic approach to
resolve both chronic vascular inflammation and dyslipidemia associated with atheroma development. In this
new application, our proposal builds on compelling evidence that epsins contribute to hyperlipidemia by
enhancing sterol regulatory element binding protein (SREBP) transcriptional activity to promote cholesterol
synthesis as well as increasing low density lipoprotein receptor (LDLR) degradation to perturb oxidized lipid
clearance in the liver. By targeting liver epsins using nanoparticle-encapsulated siRNAs, we hope to design a
novel therapeutic strategy to impede dyslipidemia in atherosclerosis. We will investigate the following Specific
Aims using unique mutant mice, in vitro models, and novel reagents: 1) to determine the molecular
mechanisms by which liver epsins regulate SREBPs in atherosclerosis, 2) to determine the molecular
mechanisms of liver epsin-mediated downregulation of LDLR in atherosclerosis, and 3) to determine the
therapeutic potential of targeting liver epsins for atheroma resolution. If fruitful, our findings will uncover original
roles for liver epsins in fueling hyperlipidemia in atherosclerosis, offer a new class of therapeutic strategies for
treating this disease, and inaugurate a paradigm shift in research relevant to fighting cardiovascular disease.

Grant Number: 5R01HL156362-04
NIH Institute/Center: NIH
Principal Investigator: Hong Chen