Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Among prominent risk factors, hardening of arteries resulting from endothelial cell activation and neointima hyperplasia plays a causative role in promoting atherogenicity. More importantly, in advanced atheroma, macrophage dysfunction causing excessive cell death is responsible for plaque rupture, consequential thrombosis, and ultimate stroke and myocardial infarction. However, owing to scarcity of proper molecular targets, it is widely recognized that hindering dysfunctional endothelium and macrophages to prevent atherosclerosis remains daunting. Our long-term goal is to uncover molecular mechanisms and identify fresh targets that prevent endothelial and macrophage dysfunction in hopes of offering potential new therapeutic approaches. To this end, our historical efforts have centered on examining the role of endothelial epsins in atherogenesis. In this application, we posit to explore the function of myeloid specific epsins in atherosclerosis owing to the fundamental contribution lesion macrophages make to fuel atherogenicity. The scientific premise for our aforesaid original research is in part established from an intriguing observation that epsins are upregulated in lesion macrophages. Therefore, understanding whether and how macrophage epsins critically contribute to the progression of atherosclerosis is urgently necessitated. We now create novel myeloid-specific epsins deficient mouse models and discover that myeloid-specific deficiency of epsins markedly inhibits western diet induced atherosclerosis in ApoE-/- mice. Further, epsins loss in macrophages dramatically impairs foam cell formation, hinders receptor-mediated oxLDL uptake, and perturbs actin-driven non-receptor mediated endocytosis. In parallel, loss of macrophage epsins results in elevated SR-B1, while diminished SR-B1 abrogates atheroprotective autophagy. Therefore, whether macrophage epsins inhibit autophagy by downregulating SR-B1 is an entirely novel question. To test, we propose to determine molecular mechanisms 1) by which epsins regulate lipid uptake during foam cell formation and 2) underlying epsin- mediated SR-BI degradation and autophagy attenuation in macrophages, and determine macrophage-derived pro-resolving lipid mediator biosynthesis. We anticipate that upon successful completion of the proposed studies, vast knowledge gained will advance the field encompassing how epsins regulate foam cell formation by controlling non-receptor and receptor-mediated lipid uptake, and how SR-B1 and epsins function opposingly to modulate atheroprotective autophagy in macrophages. Moreover, given extremely limited knowledge of the macrophage-derived pro-resolving lipid mediator involved in atherosclerosis, the study proposed herein is poised to provide insights into new means that can be exploited to treat atherosclerosis. If fruitful, our findings will uncover original roles for macrophage epsins in atherosclerosis, offer a new class of therapeutic strategies by targeting epsins, and inaugurate a paradigm shift in research highly relevant to fighting heart disease.
Atherosclerosis is the leading cause of heart attack and even death worldwide; a positive correlation of heart disease with the hardening of arteries and high levels of foam cells accumulating in the subendothelium accentuates their orchestrated actions in promoting atherosclerosis initiation and progression. How to impede aforesaid process through uncovering multiple newly elucidated mechanisms is a long-standing but highly medically relevant question. In current application, we will determine how inhibiting macrophage epsin prevents foam cell formation and concomitantly, decreases atheroma progression, in hope of finding new approaches to treat heart disease. Thus, our work is relevant to NIH?s mission to reduce the burdens of human disease.
