Serum Amyloid and Inflammation in Atherogenesis

血清淀粉样蛋白A（SAA）是一种炎症标志物，可预测心血管疾病事件。SAA 在代谢综合征中，水平升高，其特征是 早发心血管疾病我们最近发现，饮食胆固醇增加循环SAA水平 循环SAA水平比胆固醇水平更能预测动脉粥样硬化。 SAA主要依靠高密度脂蛋白（HDL）循环。它主要由肝脏产生， 而且还通过肝外细胞如巨噬细胞和血管平滑肌细胞。SAA拥有 蛋白聚糖结合结构域，可以作为脂蛋白和血管蛋白聚糖之间的桥梁。 载脂蛋白A-I是HDL的主要载脂蛋白，在小鼠和人的动脉粥样硬化病变中含量丰富， 在那里它与SAA和蛋白聚糖共定位。这些观察结果表明，HDL的保留， 血管内膜中SAA可能抑制HDL的抗动脉粥样硬化作用，并参与动脉粥样硬化的形成。 我们认为SAA是动脉粥样硬化的一种介质而不是标志物， 增加循环SAA水平，如饮食胆固醇和代谢综合征，可能会促进 通过促进脂蛋白（包括HDL）与血管蛋白聚糖的结合来抑制动脉粥样硬化。 因此，我们计划（1）进一步研究调节SAA水平的饮食和代谢因素 为了确定SAA水平升高对动脉粥样硬化的影响，（2）确定哪些亚型 的SAA由血管平滑肌细胞和巨噬细胞产生， 血管细胞有助于循环SAA，和（3）使用体外技术和小鼠模型， SAA是否过表达，以确定SAA是否是一个介导者，而不仅仅是一个标志物， 动脉粥样硬化 拟议的研究将提供有关调节血液中SAA水平的因素的重要信息 并使人类易患心血管疾病。他们还将确定SAA是否促进HDL 滞留在动脉壁上。

Serum amyloid A (SAA) is an inflammatory marker that predicts cardiovascular disease events. SAA levels are elevated in the metabolic syndrome, which is characterized by a markedly increased risk for premature cardiovascular disease. We recently found that dietary cholesterol increases circulating SAA levels in mice and that circulating SAA levels predict atherosclerosis better than cholesterol levels. SAA circulates predominantly on high density lipoprotein (HDL). It is produced mainly by the liver, but also by extra-hepatic cells such as macrophages and vascular smooth muscle cells. SAA has proteoglycan-binding domains that can serve as bridges between lipoproteins and vascular proteoglycans. Apo A-I, the major apolipoprotein of HDL, is abundant in atherosclerotic lesions in both mice and humans, where it co-localizes with both SAA and proteoglycans. These observations suggest that retention of HDL by SAA in the vascular intima might inhibit the atheroprotective effects of HDL and play a role in atherogenesis. We propose that SAA is a mediator rather than a marker of atherosclerosis and that factors that increase circulating SAA levels, such as dietary cholesterol and the metabolic syndrome, might promote atherosclerosis by facilitating the binding of lipoproteins, including HDL, to vascular proteoglycans. Therefore, we plan to (1) further investigate the dietary and metabolic factors that regulate SAA levels in blood and to determine the impact of elevated SAA levels on atherosclerosis, (2) determine which isoforms of SAA are produced by vascular smooth muscle cells and macrophages and whether SAA produced by vascular cells contributes to circulating SAA, and (3) using both in vitro and techniques and mice models in which SAA is overexpressed, to establish whether SAA is a mediator rather than merely a marker of atherosclerosis. The proposed studies will provide important information about factors that regulate SAA levels in blood and predispose humans to cardiovascular disease. They will also establish whether SAA promotes HDL retention in the artery wall.