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，会导致 加速动脉粥样硬化。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症性疾病。这些 炎症过程诱发多种代谢变化，其中两种变化 这些变化特别与动脉粥样硬化有关。第一个是 细胞因子介导的急性期血清淀粉样蛋白 A (SAA) 的诱导 增加数百倍，甚至可以成为主要的载脂蛋白 高密度脂蛋白。第二个因素是急性期的伴随诱导 胞外酶 II-A 组分泌性磷脂酶 A2 (sPLA2)。与南非航空一样， sPLA2的浓度可以在炎症中增加数百倍 液体或循环。 SAA 和 sPLA2 的循环水平预测 冠状动脉疾病患者的冠状动脉事件。使用 sPLA2 过度表达转基因小鼠，直接证据表明这 即使在没有高脂肪的情况下，酶也会促进血管脂质沉积 饮食。在初步数据中，我们提供的证据表明 SAA 增加是 与血管脂质沉积有关。花费了相当多的努力 分析 SAA 和 sPLA2 对全身脂蛋白的共同影响 新陈代谢。较少强调潜在的重要作用 这些分子可以在动脉粥样硬化病变本身中发挥作用。两人都热切地 与蛋白多糖结合并在病变处积聚。蛋白聚糖结合 sPLA2 促进一系列脂蛋白的水解，特别是低密度脂蛋白，产生 促炎的生物活性实体。 SAA 可以作为辅助因子 sPLA2。此外，淀粉样蛋白 SAA 是最易形成纤维纤维的蛋白质 已知并且可以将脂蛋白捕获在此类网络中。主要假设为 该提议是 SAA 和 sPLA2 交互作用，主要是在 血管病变层面，促进动脉粥样硬化。我们建议 SAA 和 sPLA2 分别由巨噬细胞和平滑肌细胞产生， 最终对扩大和延续病变炎症很重要 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.