Atherosclerosis is a chronic disease of arterial wall caused by various genetic and environmental risk factors and is the foremost cause of mortality worldwide. Inflammation plays a critical role in atherogenesis. Protease- activated receptor 1 (Par1) that mediates the cellular effects of thrombin, a serine protease, has been reported to play an important role in inflammation. In addition, a large body of data suggests that Par1 plays an essential role in atherothrombosis. Despite the role of Par1 in inflammation and atherothrombosis and the fact that increased expression of Par1 is observed in atherosclerotic plaques, nothing is known about its role in atherogenesis. In this context, we recently discovered that thrombin induces the expression of CD36, a scavenger receptor linked to oxLDL uptake and foam cell formation, and this event requires G?12/13, Pyk2, Gab1, PKC? and ATF2 activation downstream to Par1. In addition, we found that thrombin induces the depletion of ABCA1, a reverse cholesterol transporter and attenuates cholesterol efflux. Interestingly, ABCA1 was found to exist in complex with GSK3? and, upon treatment with thrombin, it dissociates from GSK3?, associates with cullin 3, a component of E3 ligases, and undergoes degradation. Based on these novel observations, we hypothesize that thrombin-Par1 axis plays a major role in atherogenesis. To test this central hypothesis, we propose to address the following three specific aims:
Specific Aim 1 : Par1 plays a central role in atherogenesis.
Specific Aim 2 : PKC? via activating ATF2 and enhancing CD36 expression, oxLDL uptake and foam cell formation plays a crucial role in atherogenesis.
Specific Aim 3 : Overexpression of GSK3? stabilizes ABCA1, enhances cholesterol efflux and protects from atherogenesis. The results of the proposed studies will provide new mechanistic insights into the pathophysiology of atherosclerosis and explore the translational impact of thrombin-Par1 signaling in this debilitating vascular disease.
Atherosclerosis and its lesion related thrombosis are the foremost causes of myocardial infarction and stroke, which together constitute the major cause of death in the western society. Despite the importance of thrombin in thrombus formation, its role in atherogenesis is not known. Towards this end, the experiments proposed in this grant application will provide novel insights on the involvement of thrombin and its receptor, Par1, in the pathophysiology of atherosclerosis.
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