Angiotensin Induced Proteoglycans in Atherosclerosis

描述（由申请人提供）：动脉粥样硬化发生和发展的机制尚未完全了解。如对滞留反应假说所述，致动脉粥样硬化脂蛋白通过与血管蛋白聚糖的相互作用滞留在内皮下空间内被认为是动脉粥样硬化发展的最早步骤之一。与蛋白聚糖结合的LDL更容易氧化，氧化的LDL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。动脉壁的动脉粥样硬化和非动脉粥样硬化区域之间的蛋白聚糖含量不同，载脂蛋白B和E与双糖蛋白聚糖表现出显著的共定位。然而，尚不清楚血管蛋白聚糖含量的改变是否先于动脉粥样硬化的发展并有助于动脉粥样硬化的发展，或者是动脉粥样硬化发展的结果。肾素血管紧张素系统（RAS）已被证明在动脉粥样硬化的发展中起关键作用。AngII，主要的生物活性肽，显然是促动脉粥样硬化的。AngII增加蛋白聚糖合成，尤其是上调双糖蛋白聚糖。大量临床试验表明，RAS的抑制对心血管疾病事件和风险因素具有广泛的影响，包括降低死亡、心肌梗死、中风、糖尿病和肾衰竭的风险。在初步研究中，我们表明，血管紧张素II输注诱导主动脉双糖蛋白含量增加，血管LDL滞留增加，并加速动脉粥样硬化。这项资助的总体目标是检验angll诱导双糖链蛋白聚糖含量在动脉粥样硬化的起始中起关键作用的假设。这将在具有增加的angll水平的动脉粥样硬化的小鼠模型中进行测试，并且使用双糖蛋白聚糖缺陷小鼠。一个主要的焦点是确定angll诱导双糖链的机制。美国动脉粥样硬化性心血管疾病的患病率非常高。本申请中的实验结果将确立对滞留假说的反应在动脉粥样硬化发展中的作用，证明RAS与动脉粥样硬化的联系机制，并鉴定用于干预以减少血管脂蛋白滞留作为预防动脉粥样硬化的策略的新靶点。

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.