Angll and PPARy/LXR in Atherosclerosis

描述（由申请人提供）：血管紧张素II（AngII）是一种重要的心血管风险因素，临床试验证明了与靶向肾素-血管紧张素系统（RAS）的药物相关的事件和死亡率降低，其中心血管保护作用的发生与血压降低无关。在动脉粥样硬化易感小鼠中，AngII显著加速复杂病变形成，其类似于人类中的晚期斑块。然而，AngII在体内促进更侵袭性和晚期动脉粥样硬化的机制是未知的。来自我们实验室的令人兴奋的新数据表明，AngII抑制ABCA 1的表达，ABCA 1是一种负责从泡沫细胞中去除胆固醇（即胆固醇反向转运）的关键蛋白，可防止动脉粥样硬化。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-γ（PPARgamma）的配体基本上减弱了小鼠中AngII加速的动脉粥样硬化。PPARy配体已经充分描述了抗炎活性，这可能有助于它们抑制动脉粥样硬化的活性。最近，PPARgamma配体已显示增加肝X受体α（LXR α）的巨噬细胞水平，所述肝X受体α是上调ABCA 1表达的主要转录因子。旨在阐明AngII与PPARgamma/LXR alpha的竞争性血管效应的研究可能产生新的机制见解，从而设计具有更大心血管功效的新核受体药物。在本申请中，我们假设ABCA 1的下调有助于AngII加速的动脉粥样硬化，并且PPARgamma和/或LXR α配体对巨噬细胞ABCA 1的保护可以防止动脉粥样硬化病变的发展和/或促进动脉粥样硬化病变的消退。检验该假设的具体目的是：1）确定Angfl抑制ABCA 1转录的机制和PPARgamma配体逆转该过程的能力。2)确定PPARgamma配体是否逆转AngII对ABCA 1的抑制及其对具有和不具有PPARnull单核细胞的AngII加速模型中动脉粥样硬化的最终作用？而LXR α为空。3)通过在单核细胞/巨噬细胞中过度表达野生型或显性阴性Fra 2的转基因小鼠，确定Fra 2在ABCA 1调节和动脉粥样硬化中的作用。4)确定PPARgamma配体或LXRa α配体是否可以诱导已建立的动脉粥样硬化消退。

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.