Angll and PPARy/LXR in Atherosclerosis

说明(申请人提供)：血管紧张素II(Ang11)是一种重要的心血管危险因素，临床试验表明，针对肾素-血管紧张素系统(RAS)的药物减少了事件和死亡率，其中心血管保护作用与降压无关。在易患动脉粥样硬化的小鼠中，Angll显著加速复杂病变的形成，这类似于人类的高级斑块。然而，血管紧张素转换酶促进体内更具侵袭性和进展性动脉粥样硬化的机制(S)尚不清楚。来自我们实验室的令人兴奋的新数据表明，Ang11抑制ABCA1的表达，ABCA1是负责从泡沫细胞中去除胆固醇(即反向胆固醇运输)的关键蛋白质，可以防止动脉粥样硬化。我们还发现，目前用于治疗2型糖尿病的核受体过氧化物酶体增殖物激活受体-伽马(PPARGamma)的配体显著减轻了Angll加速的小鼠动脉粥样硬化。PPARGamma，配体有很好的抗炎活性，这可能有助于它们抑制动脉粥样硬化的活性。最近，PPARGamma配体被证明可以增加巨噬细胞肝脏X受体α(LXRpha)的水平，LXRpha是上调ABCA1表达的主要转录因子。旨在阐明Angll和PPARGamma/LXRpha相互竞争的血管效应的研究可能会产生新的机制见解，从而设计出具有更大心血管功效的新核受体药物。在这一应用中，我们假设ABCA1的下调有助于Ang11加速的动脉粥样硬化，并且PPARGamma和/或LXRpha配体保存巨噬细胞ABCA1可能防止和/或促进动脉粥样硬化病变的发展和/或消退。验证这一假说的具体目的是：1)确定Angf1抑制ABCA 1转录的机制以及PPARγ配体逆转这一过程的能力。2)在单核细胞PPAR阴性和不伴有PPAR阴性的Ang11加速模型中，确定PPARγ是否能逆转ABCA 1的Angll抑制及其对动脉粥样硬化的最终作用？对于LXRAlpha，则为空。3)建立在单核/巨噬细胞中高表达野生型或显性阴性FRA2的转基因小鼠，以确定FRA2在ABCA1调节和动脉粥样硬化中的作用。4)确定PPARGamma配体或LXRapha配体是否能诱导已建立的动脉粥样硬化的消退。

DESCRIPTION (provided by applicant): 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.