SAA and sPLA2 Role in Atherogenesis

描述（由申请人提供）： 慢性炎症性疾病，特别是风湿性疾病，导致 加速动脉粥样硬化与此同时，动脉粥样硬化本身 越来越多地被认为是一种慢性血管炎性疾病。这些 炎症过程诱导多种代谢变化，其中两种 这些变化与动脉粥样硬化形成密切相关。首先是 细胞因子介导的急性期血清淀粉样蛋白A（SAA）诱导， 增加数百倍，甚至可以成为主要的载脂蛋白， HDL。第二个因素是急性期的伴随诱导 胞外酶II-A族分泌型磷脂酶A2（sPLA 2）。和SAA一样， sPLA 2浓度在炎症中可增加数百倍， 液体或循环。SAA和sPLA 2的循环水平预测 冠心病患者的冠状动脉事件。使用sPLA 2 过表达转基因小鼠，直接证据表明， 酶促进血管脂质沉积，即使在没有高脂肪的情况下， 饮食.在初步数据中，我们提出的证据表明，增加SAA是 与血管脂质沉积有关。花了相当大的努力 分析SAA和sPLA 2对系统脂蛋白的共同影响 新陈代谢.对潜在的重要作用的强调较少， 这些分子本身可在动脉粥样硬化损伤中起作用。两人贪婪地 与蛋白聚糖结合并在病变中积累。蛋白多糖结合型sPLA 2 促进脂蛋白谱的水解，特别是LDL，产生 促炎的生物活性物质。SAA可以作为辅助因子， sPLA2。此外，淀粉样蛋白生成性SAA是最具纤维形成性的蛋白质， 已知的并且可以在这样的网络中捕获脂蛋白。的主要假设 这一建议是SAA和sPLA 2相互作用，主要在 血管病变水平，促进动脉粥样硬化形成。我们建议SAA和 sPLA 2分别由巨噬细胞和平滑肌细胞产生， 重要的是扩大和延续病变炎症， 促进血管脂质沉积。

DESCRIPTION (provided by applicant): Chronic inflammatory diseases, particularly rheumatic diseases, lead to accelerated atherosclerosis. At the same time, atherosclerosis itself is increasingly recognized as a chronic vascular inflammatory condition. These inflammatory processes induce a wide variety of metabolic changes with two of these changes relating specifically to atherogenesis. The first is the cytokine mediated induction of acute phase serum amyloid A protein (SAA) that increases hundreds of fold and can even become the major apolipoprotein on HDL. A second factor is the concomitant induction of an acute phase extracellular enzyme group II-A secretory phospholipase A2 (sPLA2). Like SAA, the concentration of sPLA2 can increase hundreds of fold in inflammatory fluids or the circulation. Circulating levels of both SAA and sPLA2 predict coronary events in patients with coronary artery disease. Using sPLA2 overexpressing transgenic mouse, direct evidence was presented that this enzyme promotes vascular lipid deposition, even in the absence of a high fat diet. In preliminary data, we present evidence that increased SAA is associated with vascular lipid deposition. Considerable effort was spent analyzing the concomitant influence of SAA and sPLA2 on systemic lipoprotein metabolism. Less emphasis was placed on the potentially important role that these molecules can play in the atherosclerotic lesion per se. Both avidly bind to proteoglycan and accumulate in lesions. Proteoglycan bound sPLA2 promote hydrolysis of a spectrum of lipoproteins, particularly LDL, generating bioactive entities that are proinflammatory. SAA can act as a co-factor for sPLA2. In addition amyloidogenic SAAs are the most fibrillogenic proteins known and can entrap lipoprotein in such networks. The major hypothesis of this proposal is that SAA and sPLA2 act interactively, predominantly at the vascular lesional level, to promote atherogenesis. We propose that SAA and sPLA2, respectively produced by macrophages and smooth muscle cells, is important in amplifying and perpetuating lesional inflammation ultimately promoting vascular lipid deposition.