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。与此同时，动脉粥样硬化本身 越来越多的人认为这是一种慢性血管炎症。这些 炎症过程引起各种各样的代谢变化，其中两种 这些变化特别与动脉粥样硬化的形成有关。第一个是 细胞因子介导的急性时相血清淀粉样蛋白A的诱导 增加了数百倍，甚至可以成为主要的载脂蛋白 高密度脂蛋白。第二个因素是伴随而来的急性期的诱导 胞外酶II-A分泌型磷脂酶A2(SPLA2)。像SAA一样， SPLA2在炎症中的浓度可以增加数百倍 体液或血液循环。循环中SAA和sPLA2水平均可预测 冠心病患者的冠状动脉事件。使用sPLA2 过度表达转基因小鼠，有直接证据表明这 酶促进血管脂肪沉积，即使在没有高脂肪的情况下也是如此 节食。在初步数据中，我们提出了增加的SAA是 与血管脂肪沉积有关。花费了相当大的努力 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，即 这些分子本身可以在动脉粥样硬化病变中发挥作用。两人都热衷于 结合蛋白多糖，并在皮损中蓄积。蛋白多糖结合sPLA2 促进一系列脂蛋白的水解，特别是低密度脂蛋白，产生 具有促炎作用的生物活性实体。SAA可以作为一个共同因素 SPLA2。此外，淀粉样变性SaaS是纤维蛋白原最多的蛋白质 已知并能将脂蛋白包埋在这样的网络中。的主要假说 这个建议是SAA和SPLA2相互作用，主要是在 血管病变水平，促进动脉粥样硬化形成。我们建议SAA和 SPLA2分别由巨噬细胞和平滑肌细胞产生，是 在最终放大和持久皮损炎症中起重要作用 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.