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.
Our long-term goal is to understand the cellular events that underlie the formation and growth of unstable atherosclerotic plaques in the arterial wall, which can cause heart attacks and strokes and represent the leading cause of death worldwide and are highly-relevant to the mission of the NIH. These vulnerable plaques are largely composed of macrophages and lipids deposited in the sub-endothelial layer of arteries resulting from chronic inflammation and endothelial cell injury or dysfunction. Because the liver is the primary site of lipid synthesis, we are unraveling the molecular mechanisms responsible for the activation of deleterious cell signaling pathways in the liver in an effort to identify new therapeutic targets to treat atherosclerosis.