ELEVATED SERUM AMYLOID A CONTRIBUTES TO OBESITY-INDUCED ATHEROSCLEROSIS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 临床研究表明血清淀粉样蛋白A（SAA）水平升高与心血管事件风险增加之间存在相关性。 此外，SAA水平升高也与肥胖相关，肥胖是心血管疾病的重要风险因素。 先前的研究表明，血浆SAA浓度与高脂血症小鼠动脉粥样硬化病变大小相关。 初步数据表明，SAA在apoE-/-小鼠中的过表达增加动脉粥样硬化。 为了研究肥胖对动脉粥样硬化的影响，我们在apoE-/-小鼠中建立了饮食诱导的肥胖模型。 在该模型中，肥胖的诱导和动脉粥样硬化的增加与血浆和脂肪组织SAA浓度的增加相关。 与瘦型小鼠相比，肥胖型apoE-/-小鼠中大比例的血浆SAA与促动脉粥样硬化脂蛋白VLDL和LDL结合，瘦型小鼠中SAA主要与HDL相关。脂蛋白与内皮下蛋白多糖结合，增加了脂蛋白在血管壁的滞留，促进了动脉粥样硬化的发展。 SAA富集的HDL增加了与蛋白聚糖的结合。因此，SAA富集VLDL和LDL可能通过增加脂蛋白在血管壁中的滞留和促进泡沫细胞形成而促进动脉粥样硬化。 因此，我们认为肥胖诱导的炎症增加了脂肪SAA的产生，从而增加了apoe-/-小鼠的动脉粥样硬化。 为了检验这一假设，我们提出：1）确定在肥胖期间浸润脂肪组织的脂肪细胞和/或巨噬细胞是否是脂肪组织SAA表达增加的来源。 2)确定是否巨噬细胞浸润的脂肪组织调节SAA脂肪细胞的表达。3)确定SAA富集致动脉粥样硬化脂蛋白是否增加蛋白聚糖结合，从而促进巨噬细胞泡沫细胞形成。 4)确定SAA缺乏是否减弱肥胖诱导的动脉粥样硬化病变形成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clinical studies have demonstrated an association between elevated levels of serum amyloid A (SAA) and increased risk of cardiovascular events. Moreover, elevated levels of SAA are also associated with obesity which is a significant risk factor for cardiovascular disease. Previous studies have demonstrated that plasma SAA concentrations correlate with atherosclerotic lesion size in hyperlipidemic mice. Preliminary data demonstrate that overexpression of SAA in apoE-/- mice increases atherosclerosis. To study the effect of obesity on atherosclerosis we have generated a model of diet induced obesity in apoE-/- mice. The induction of obesity and increase in atherosclerosis in this model are associated with an increase in plasma and adipose tissue SAA concentrations. A large percentage of plasma SAA was bound to the pro-atherogenic lipoproteins, VLDL and LDL, in obese apoE-/- mice compared to lean, in which SAA is primarily associated with HDL. Lipoprotein binding to proteoglycans in the subendothelial space is suggested to increase lipoprotein retention in the vascular wall and facilitate the development of atherosclerosis. SAA enriched HDL has increased binding to proteoglycans. Thus, SAA enrichment of VLDL and LDL may promote atherosclerosis by increasing lipoprotein retention in the vascular wall and facilitating foam cell formation. Therefore we propose that obesity induced inflammation augments adipose SAA production to increase atherosclerosis in apoE-/- mice. To test this hypothesis we propose to: 1) Determine if adipocytes and/or macrophages infiltrating the adipose tissue during obesity are the source of increased adipose tissue SAA expression. 2) Determine if macrophages infiltrating the adipose tissue regulate SAA adipocyte expression. 3) Determine if SAA enrichment of pro-atherogenic lipoproteins increases proteoglycan binding, thus facilitating macrophage foam cell formation. 4) Determine if SAA deficiency attenuates obesity-induced atherosclerotic lesion formation.