Angiotensin II (Angll) is an important cardiovascular risk factor as evidenced by clinical trials demonstrating decreased events and mortality associated with drugs targeting the renin-angiotensin system (RAS), in which cardiovascular protection occurred independent of blood pressure lowering. In atherosclerosis-prone mice, Angll markedly accelerates complex lesion formation, which resembles advanced plaques in humans. However, the mechanism(s) by which Angll promotes more aggressive and advanced atherosclerosis in vivo is unknown. Exciting new data from our laboratory suggests that Angll suppresses expression of ABCA1, a key protein responsible for removal of cholesterol from foam cells (i.e. reverse cholesterol transport) that protects against atherosclerosis. We also find that ligands for the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma), currently used for the treatment of type 2 diabetes, substantially attenuate Angll-accelerated atherosclerosis in mice. PPARgamma, ligands have well described anti-inflammatory activity which likely contributes to their activity to inhibit atherosclerosis. Recently, PPARgamma ligands have been shown to increase macrophage levels of the liver X receptor alpha (LXRalpha) a major transcription factor up regulating ABCA1 expression. Studies designed to elucidate the competing vascular effects of Angll with PPARgamma/LXRalpha may yield new mechanistic insights leading to the design of new nuclear receptor drugs with greater cardiovascular efficacy. In this application, we hypothesize that down regulation of ABCA1 contributes to Angll-accelerated atherosclerosis and that preservation of macrophage ABCA1 by PPARgamma, and/or LXRalpha ligands may prevent the development of and/or promote the regression of atherosclerotic lesions.
Specific Aims to test this hypothesis are: 1) Determine the mechanisms by which Angfl represses ABCA 1 transcription and the ability of PPARgamma ligands to reverse this process. 2) Determine whether PPARgamma Iigands reverse Angll suppression of ABCA 1 and its ultimate effect on atherosclerosis in Angll accelerated models with and without monocytes null for PPAR? and null for LXRalpha. 3) Determine the role of Fra 2 in ABCA1 regulation and atherosclerosis by developing transgenic mice overexpressing either wild-type or dominant-negative Fra 2 in monocytes/macrophages. 4) Determine whether PPARgamma ligands or LXRaalpha ligands can induce regression of established atherosclerosis.
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