Angiotensin Induced Proteoglycans in Atherosclerosis

动脉粥样硬化中血管紧张素诱导的蛋白多糖

• 批准号: 7879773
• 负责人: LISA R TANNOCK
• 金额: $ 27.38万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879773
• 关键词: AGTR2 gene; Angiotensins; Animals; Apolipoproteins; Apolipoproteins B; Arteries; Atherosclerosis; Attenuated; Binding; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical Trials; Data; Development; Diabetes Mellitus; Employee Strikes; Event; Foam Cells; Goals; Grant; High Prevalence; Human; In Vitro; Infusion procedures; Intervention; Kidney Failure; Link; Lipoproteins; Low-Density Lipoproteins; Mediating; Modeling; Mus; Myocardial Infarction; Peptides; Play; Proteoglycan; Relative (related person); Renin-Angiotensin System; Research Personnel; Risk; Risk Factors; Role; Saline; Smooth Muscle Myocytes; Stroke; Testing; Transcriptional Regulation; biglycan; in vivo; macrophage; mouse model; novel; oxidation; oxidized low density lipoprotein; prevent; programs; promoter; protective effect; receptor; research study; response

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.

描述（由申请人提供）：动脉粥样硬化发生和发展的机制尚不完全清楚。正如对保留假说的反应所概述的那样，通过与血管蛋白聚糖的相互作用，致动脉粥样硬化脂蛋白在内皮下空间的保留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更易被氧化，氧化后的LDL被巨噬细胞或平滑肌细胞大量摄取，导致泡沫细胞的形成。在动脉壁的动脉粥样硬化区和非动脉粥样硬化区，蛋白聚糖含量不同，载脂蛋白B和E与高聚糖具有显著的共定位。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促成了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。Angll，主要的生物活性肽，显然是促动脉粥样硬化的。Angll增加蛋白多糖的合成，尤其是上调高聚糖。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、糖尿病和肾衰竭的风险。在初步研究中，我们发现angll输注导致主动脉多糖含量增加，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验证angll诱导多糖含量在动脉粥样硬化的发生中起关键作用的假设。这将在angll水平升高的动脉粥样硬化小鼠模型中进行测试，并使用biglycan缺乏的小鼠。一个主要的焦点是确定角诱导大聚糖的机制。美国的动脉粥样硬化性心血管疾病发病率非常高。本应用的实验结果将确立响应保留假说在动脉粥样硬化发展中的作用，证明RAS与动脉粥样硬化之间的联系机制，并确定新的干预靶点，以减少血管脂蛋白保留，作为预防动脉粥样硬化的策略。