The arterial inflammatory responses initiated by the oxidation of LDL trapped in the subendothelium are a key process that drives the initiation, progression, and even rupture of atherosclerotic plaques. However, there have been no effective medicines or therapies available to disrupt the inflammatory process due to lack of appropriate targets. Epsins are a group of proteins that bind clathrin and are involved in the endocytosis of clathrin-coated vesicles. Our studies have shown that epsins expressed in endothelial cells play a major role in the pathogenesis of atherosclerosis. Deletion of the epsin 1 (Epn1) and epsin 2 (Epn2) genes in endothelial cells results in a dramatic reduction in atherosclerotic lesion sizes in apolipoprotein E-deficient (ApoE-/-) mice without affecting systemic hypercholesterolemia. We have also observed that knockdown of both Epn1 and Epn2 with siRNAs affects NF-kB signaling transduction and suppresses both baseline and TNFa-induced VCAM-1 and P-selectin expression in endothelial cells. Therefore, we hypothesize that epsins critically regulate arterial inflammatory responses and consequently potentiate atherosclerotic plaque formation by enhancing TNF-induced NF-kB activation. The role of epsins 1 and 2 in atherosclerosis and molecular mechanisms underlying the arterial inflammatory processes will be characterized using both in vitro and in vivo model systems.
In Aim 1, we will investigate molecular mechanisms by which epsins enhance TNF-induced NF-kB signaling in endothelial cells.
In Aim 2, we will utilize multifactorial approaches employing both flow cytometry and immunohistochemistry and immunofluorescence to investigate how epsins promote atherogenesis by potentiating endothelial cell activation. These studies will provide mechanistic links between epsins and plaque formation.
In Aim 3, we will determine whether targeting epsins in plaques impedes atheroma progression in ApoE-/- mice. These studies will shed light on new pathways that control atherosclerosis and may lead to new treatment of atherosclerosis.
Atherosclerosis is the most common cause of death in the United States. Acute rupture and thrombosis of the atherothrombotic plaque is a dangerous condition that leads to heart attack, stroke and peripheral tissue ischemia. In current application we will define how a novel signaling adaptor protein, epsin controls the development of atherosclerosis by regulating arterial wall inflammation. The findings will provide useful information on developing key reagents to advance the epsin-based targeting strategy for therapeutic intervention of atherosclerosis.
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