The Acute Phase Response in Atherosclerosis

描述(由申请人提供)：越来越多的证据支持炎症在动脉粥样硬化发展中的重要作用。动脉粥样硬化性病变的发展在一定程度上是由炎症介质的作用引导的，在表面上健康的受试者中，全身炎症标志物的存在与随后发生的心血管疾病呈正相关。然而，系统性炎症在动脉粥样硬化发展中的作用还不是很清楚。全身炎症的主要组成部分，急性时相反应(APR)，分两个阶段触发。第一阶段导致损伤部位产生促炎细胞因子，如IL-1β、肿瘤坏死因子α(TNFpha)和IL-6。第二阶段涉及这些细胞因子对肝脏等靶器官的作用，在那里急性时相蛋白的合成受到刺激或抑制。IL-6是未来心肌梗死风险增加的指标，它主要通过转录因子STAT3对APR基因产生影响。STAT3被表达为两种具有不同生化特性的异构体。选择性剪接受体位点的使用指定了Stat3beta(Stat 3beta)亚型。我们使用了一种新的方法来产生选择性不能合成Stat3β亚型的小鼠。我们的初步观察揭示了Stat3β在STAT3介导的转录调控中的作用，并表明Stat3β对于全身炎症的正常恢复是必不可少的。为了探讨STAT3亚型在调节急性期反应中的作用，以及急性期反应与动脉粥样硬化的关系，我们将追求三个目标。我们将通过全基因组微阵列分析，开发正常和Stat3b缺陷小鼠肝脏和内皮急性期反应的详细转录图谱。使用生化和计算方法的组合，我们将定义Stat3beta如何调节STAT3反应基因的表达。第三，我们将通过检测Stat3β缺乏对小鼠动脉粥样硬化发展的影响来检验慢性全身炎症促进动脉粥样硬化发展的假说。

DESCRIPTION (provided by applicant): A growing body of evidence supports a prominent role for inflammation in the development of atherosclerosis. The evolution of atheromatous lesions is guided in part by the action of inflammatory mediators, and in apparently healthy subjects, the presence of systemic inflammatory markers is positively correlated with the subsequent occurrence of cardiovascular disease. Nonetheless, the contributions of systemic inflammation to development of atherosclerosis are not well understood. The major component of systemic inflammation, the acute phase response (APR), is triggered in two phases. The first phase leads to the production of proinflammatory cytokines such as IL-lbeta, tumor necrosis factor alpha (TNFalpha) and IL-6 at the site of injury. The second phase involves the action of those cytokines on target organs such as the liver, where synthesis of acute phase proteins is stimulated or suppressed. IL-6, an indicator of increased risk for future myocardial infarction, exerts its effects on APR genes principally through the transcription factor Stat3. Stat3 is expressed as two isoforms with distinct biochemical properties. The use of an alternative splice acceptor site specifies the Stat3beta (Stat 3beta) isoform. We have used a novel approach to generate mice that are selectively unable to synthesize the Stat3beta isoform. Our preliminary observations uncover a role for Stat3beta in the modulation of Stat3-mediated transcription, and suggest that Stat3beta is essential for normal recovery from systemic inflammation. To explore the role of Stat3 isoforms in the regulation of the acute phase response, and the relation of the acute phase response to atherosclerosis, we will pursue three aims. We will develop detailed transcriptional maps of the hepatic and endothelial acute phase responses in normal and Stat3b-deficient mice by genome-wide microarray assays. Using a combination of biochemical and computational approaches, we will define how Stat3beta modulates expression of Stat3-responsive genes. Third, we will test the hypothesis that chronic systemic inflammation promotes development of atherosclerosis by examining the influence of Stat3beta-deficiency on development of atherosclerosis in mouse models.