Role of Serum Amyloid A in Atheroscierosis

心血管疾病是#年的主要死亡原因。 发达国家。患有肥胖症、代谢综合征和/或糖尿病的人明显 动脉粥样硬化性心血管疾病的风险增加，尽管潜在的机制还不完全 明白了。动脉壁内皮下间隙内致动脉粥样硬化脂蛋白的滞留 它们与血管蛋白多糖的相互作用被认为是启动动脉粥样硬化的关键步骤， 正如“对保留的反应假说”中所概述的。肥胖、代谢综合征和糖尿病 与包括血清淀粉样蛋白A(SAA)和SAA在内的炎症标志物水平的升高有关 在人类和动物模型中，水平是心血管疾病的预测指标。的中心假说 这项资助是SAA是促动脉粥样硬化的。这一假设基于几个关键观察：(A)SAA是 在动脉粥样硬化病变中与载脂蛋白和蛋白多糖密切相关；(B)我们 最近证明SAA以促进动脉粥样硬化的方式改变血管蛋白多糖的合成；(C) SAA是一种载脂蛋白，能够与蛋白多糖结合，因此可能有助于保留 (D)在初步研究中，我们证实动脉粥样硬化在 SAA过度表达的小鼠。因此，SAA实际上可能是动脉粥样硬化的介质，它通过导致 血管蛋白多糖增加致动脉粥样硬化脂蛋白的滞留。我们将通过以下方式验证这一假设 评价SAA过表达对血管蛋白多糖合成、脂蛋白滞留和血管功能的影响 用活体方法学研究动脉粥样硬化的发展。鉴于观察到的SAA水平在 肥胖、代谢综合征和糖尿病，我们认为SAA可能是导致 在这些情况下，心血管疾病增加。 项目主任/首席调查员(最后、第一、中间)：TANNOCK，Lisa R.

Cardiovascular disease is the leading cause of death in developed countries. Individuals with obesity, metabolic syndrome, and/or diabetes are at markedly increased risk of atherosclerotic cardiovascular disease although the underlying mechanisms are not fully understood. The retention of atherogenic lipoproteins within the subendothelial space of the arterial wall by their interactions with vascular proteoglycans is thought to be a key step in the initiation of atherosclerosis, as outlined in the “Response to Retention Hypothesis”. Obesity, the metabolic syndrome and diabetes all are associated with increased levels of inflammatory markers including serum amyloid A (SAA), and SAA levels are predictive of cardiovascular disease in humans and in animal models. The central hypothesis of this grant is that SAA is pro-atherogenic. This hypothesis is based on several key observations: (a) SAA is present within atherosclerotic lesions in close association to apolipoproteins and proteoglycans; (b) We recently demonstrated that SAA alters vascular proteoglycan synthesis in a pro-atherogenic manner; (c) SAA is an apolipoprotein that is capable of binding to proteoglycans, and thus may facilitate the retention of lipoproteins on which it is carried; (d) In preliminary studies we demonstrate accelerated atherosclerosis in mice in which SAA is over-expressed. Thus, SAA may in fact be a mediator of atherosclerosis by leading to increased retention of atherogenic lipoproteins by vascular proteoglycans. We will test this hypothesis by evaluating the effect of SAA over-expression on vascular proteoglycan synthesis, lipoprotein retention and atherosclerosis development using in vivo methodology. Given the increased SAA levels observed in obesity, metabolic syndrome and diabetes, we propose that SAA may be a mechanism contributing to the increased cardiovascular disease in these conditions. Program Director/Principal Investigator (Last, First, Middle): Tannock, Lisa R.