Role of PAI-1 in Venous Thrombosis

静脉血栓栓塞（DVT/PE）是一个主要的医疗保健问题， mortality.根据AHA的数据，每年有多达200万美国人受到深静脉血栓的影响。 血栓形成（DVT），每年有20万人死于其并发症之一肺栓塞（PE）， 比乳腺癌和艾滋病加起来还要多我们和其他人已经证明， 反应发生静脉血栓栓塞，这种炎症，通过生产 促凝血微粒，导致血栓放大。纤溶酶原激活物抑制剂-1（派-1）是 血浆中纤溶酶原激活物的主要抑制剂。它以活性形式从肝脏分泌， 内皮细胞，并通过与玻连蛋白结合而稳定。它能使组织纤溶酶原激活剂 (tPA)和尿激酶型纤溶酶原激活物（uPA）。派-1水平因高脂血症而升高， 派-1升高似乎与凝血因子V Leiden基因异常协同作用，凝血因子V Leiden基因异常是一种血栓性突变， 因子V（Leiden），其使其抵抗蛋白水解降解。派-1的升高可能与 可抑制纤维蛋白溶解并增加血栓形成。研究派-1水平升高对 静脉血栓形成一直是矛盾的。本提案的目的是确定派-1的作用 在鼠完全IVC结扎静脉血栓形成模型（aim 1a）和鼠完全IVC结扎静脉血栓形成模型（aim 1b）中静脉血栓形成中， IVC狭窄诱导的静脉血栓形成模型（目的1b）。派-1缺失和派-1过表达小鼠 将被研究，玻连蛋白缺陷小鼠，派-1/玻连蛋白联合缺陷小鼠， 和野生型小鼠。我们还将使用药理学派-1抑制。血栓形成，静脉壁/血栓 炎症，促凝血微粒的产生，以及血栓/静脉壁纤维化将是可能的。 评估。此外，我们将确定血栓形成后派-1抑制的功效， 纤溶酶的产生，以及凝血酶在两种模型中静脉血栓形成中的作用（AIM 1C）。最后我们将 研究因子V Leiden杂合和纯合小鼠，ApoE高脂血症小鼠， Egr-1缺失小鼠（派-1启动子区的Egr-1位点是由缺氧诱导的，这是静脉缺氧的特征 停滞）和野生型小鼠（目的2a，2b）。这些派-1水平将与 血栓形成该建议的结果应更好地定义派-1在静脉血栓形成中的作用。

Venous thromboembolism (DVT/PE) is a major healthcare problem causing significant morbidity and mortality. According to the AHA, up to two million Americans are affected annually by deep venous thrombosis (DVT) and 200,000 die annually from one of its complications, pulmonary embolism (PE), more than breast cancer and AIDs combined. We and others have demonstrated that a significant inflammatory response occurs with venous thromboembolism and that this inflammation, through the production of procoagulant microparticles, leads to thrombus amplification. Plasminogen Activator lnhibitor-1 (PAI-1) is the primary inhibitor of plasminogen activators in plasma. It is secreted in an active form from liver and endothelial cells and is stabilized by binding to vitronectin. It inactivats both tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). PAI-1 levels are elevated by hyperlipidemia, and PAI-1 elevation appears to synergize with Factor V Leiden genetic abnormalities, a thrombophilic mutation of Factor V (Leiden) which renders it resistent to proteolytic degradation. It is plausible that elevated PAI-1 could suppress fibrinolysis and increase thrombosis. Studies on the role of elevated levels of PAI-1 to venous thrombosis have been contradictory. The purpose of this proposal is to determine the role of PAI-1 in venous thrombogenesis in a murine complete IVC ligtion venous thrombosis model (aim 1a) and a murine IVC stenosis-induced venous thrombosis model (aim 1b). Mice with PAI-1 deletion and PAI-1 overexpression will be studied, as will vitronectin deficient mice, mice with combined PAI-1/vitronectin deficiency, and wild type mice. We will also use pharmacologic PAI-1 inhibition. Thrombogenesis, vein wall/thrombus inflammation, the production of procoagulant microparticles, and thrombus/vein wall fibrosis will be evaluated. Additionally, we will determine the efficacy of PAI-1 inhibition after thrombogenesis, the roles of plasmin generation, and the role of thrombin in venous thrombosis in both models (aim 1c). Finally, we will study levels of PAI-1 in Factor V Leiden heterozygous and homozygous mice, ApoE hyperlipidemic mice, Egr-1 null mice (the Egr-1 site in the PAI-1 promoter region is induced by hypoxia, a characteristic of venous stasis), and wild type mice in both models (aims 2a, 2b). These levels of PAI-1 will be correlated to thrombosis. The results of this proposal should better define the role of PAI-1 in venous thrombogenesis.