Angiotensin Induced Proteoglycans in Atherosclerosis

描述(由申请人提供)：动脉粥样硬化的发生和发展的机制还不完全清楚。如《对滞留的反应假说》所述，致动脉粥样硬化的脂蛋白通过与血管蛋白多糖的相互作用滞留在内皮下间隙中被认为是动脉粥样硬化发展的最早步骤之一。与蛋白多糖结合的低密度脂蛋白更容易被氧化，氧化的低密度脂蛋白被巨噬细胞或平滑肌细胞贪婪地摄取，导致泡沫细胞的形成。动脉壁动脉粥样硬化区和非动脉粥样硬化区的蛋白多糖含量不同，载脂蛋白B和E与Biglycan显示出显著的共同定位。然而，目前尚不清楚血管蛋白多糖含量的改变是在动脉粥样硬化的发展之前并促进其发展，还是动脉粥样硬化的发展的结果。肾素血管紧张素系统(RAS)已被证明在动脉粥样硬化的发生发展中起关键作用。血管紧张素转换酶是主要的生物活性多肽，显然是促动脉粥样硬化的。血管紧张素转换酶促进蛋白多糖的合成，尤其是上调二聚糖的合成。大量临床试验表明，抑制RAS对心血管疾病事件和危险因素有广泛的影响，包括降低死亡、心肌梗死、中风、糖尿病和肾功能衰竭的风险。在初步研究中，我们发现血管紧张素转换酶抑制剂可导致主动脉中二聚糖含量增加，血管内低密度脂蛋白滞留增加，并加速动脉粥样硬化。这项拨款的总体目标是测试这一假说，即血管紧张素转换酶诱导的双聚糖含量在动脉粥样硬化的启动中起着关键作用。这将在血管紧张素水平升高的动脉粥样硬化小鼠模型中进行测试，并使用胆聚糖缺乏的小鼠。一个主要的焦点是确定血管紧张素转换酶诱导巨聚糖的机制。美国动脉粥样硬化性心血管疾病的患病率非常高。这一应用中的实验结果将确立对滞留的反应假说在动脉粥样硬化发展中的作用，展示RAS与动脉粥样硬化的联系机制，并确定新的干预靶点，以减少血管脂蛋白滞留作为预防动脉粥样硬化的策略。

DESCRIPTION (provided by applicant): The mechanisms underlying the initiation and development of atherosclerosis are not fully understood. As outlined in the response to retention hypothesis, the retention of atherogenic lipoproteins within the sub-endothelial space by their interactions with vascular proteoglycans is thought to be one of the earliest steps in the development of atherosclerosis. LDL that is bound to proteoglycans is more susceptible to oxidation, and oxidized LDL is avidly taken up by macrophages or smooth muscle cells, leading to the formation of foam cells. Proteoglycan content differs between atherosclerotic and non-atherosclerotic regions of the artery wall, and apolipoproteins B and E demonstrate striking co-localization with biglycan. However, it is not clear if altered vascular proteoglycan content precedes and contributes to the development of atherosclerosis, or is a consequence of the development of atherosclerosis. The renin angiotensin system (RAS) has been shown to play a critical role in the development of atherosclerosis. Angll, the major biologically active peptide, is clearly pro-atherogenic. Angll increases proteoglycan synthesis, especially up- regulating biglycan. Numerous clinical trials demonstrate that inhibition of the RAS has broad impacts on cardiovascular disease events and risk factors, including decreased risk of death, myocardial infarction, stroke, diabetes mellitus and renal failure. In preliminary studies we show that angll infusion induces increased aortic biglycan content, increased vascular LDL retention, and accelerates atherosclerosis. The overall goal of this grant is to test the hypothesis that induction of biglycan content by angll plays a critical role in the initiation of atherosclerosis. This will be tested in mouse models of atherosclerosis with increased angll levels, and using biglycan deficient mice. A major focus is to identify mechanisms by which angll induces biglycan. The USA has a very high prevalence of atherosclerotic cardiovascular disease. The results of the experiments in this application will establish the role of the response to retention hypothesis in atherosclerosis development, demonstrate a mechanism linking the RAS to atherosclerosis, and identify novel targets for intervention to decrease vascular lipoprotein retention as a strategy to prevent atherosclerosis.