Recent breakthroughs in our understanding of pathobiology of atherogenesis necessitate revision of overly simplistic concept of 'good"""""""" and """"""""bad"""""""" cholesterol and suggest novel directions for the development of effective therapies. During the last few years, oxidation of low density lipoproteins (LDL) and scavenger-receptor dependent internalization of oxidized LDL (ox-LDL) by vascular cells was established to be a main factor driving atherogenesis. Endothelial monolayer is a primary component of vascular wall interacting with oxidatively modified LDL. Its activation and angiogenic responses are prerequisites for initiation and progression of atherosclerosis as well as plaque instability and eventual rupture. Our group has shown that ox-LDL internalization is mediated predominantly by a lectin-like ox-LDL receptor (LOX-1) and that ox-LDL mediated stimulation of angiogenesis is LOX-1 dependent. In our earlier studies in a murine model of hypercholesterolemia, we have also shown that abrogation of LOX-1 results in significant attenuation of atherosclerosis. Based on these findings we believe that LOX-1 may become an attractive target for therapeutic interventions. In search for approaches to inhibition of ox-LDL/endothelium interactions, we have determined microRNAs implicated in LOX-1 regulation and ox-LDL downstream signaling using physiologically realistic exposures to ox-LDL. We have also screened and identified candidate small molecules that, based on existing models of LOX-1/ox- LDL interactions, demonstrate a potential to block LOX-1 binding site. We propose to conduct studies that would evaluate miRNA and small molecules based therapies with regard to plaque angiogenesis and progression of atherosclerosis. The objectives of the current proposal are to: a) further elucidate the role of ox- LDL/LOX-1 signaling in relation to angiogenesis, and b) determine efficacy of LOX-1- centered miRNA and small molecule-based interventions in prevention of angiogenesis and atherosclerosis. The PI has been engaged in the research on LOX-1 biology for the last 15 years and his group significantly contributed to elucidation of LOX-1 biology - especially in relation to cardiovascular conditions - with more than 50 publications in major peer- reviewed journals.
Atherosclerosis is a main cause of death in the United States. One of the mechanisms responsible for development and growth of atherosclerotic plaque as well as its instability and eventual rupture is formation of new blood vessels within the plaque (angiogenesis). This process to a large degree depends on scavenger receptor LOX-1 mediated internalization of oxidized LDL by endothelial cells. We propose to develop new ways of treatment of atherosclerosis by using microRNAs (micro-ribonucleic acids that occur naturally in our bodies) and small molecules to block LOX-1 and prevent angiogenesis. We believe that our studies will lead to novel and highly effective methods for preventing many cardiovascular diseases including heart attack and stroke.
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