Role of PAI-1 in Venous THrombosis

静脉血栓栓塞症(DVT/PE)是一个主要的医疗问题，导致显著的发病率和 死亡率。根据AHA的数据，每年有多达200万美国人受到深静脉疾病的影响 血栓形成(DVT)，每年有20万人死于其并发症之一-肺栓塞(PE)，更多 比乳腺癌和艾滋病加起来还多。我们和其他人已经证明了显著的炎症性 反应发生在静脉血栓栓塞症和这种炎症，通过产生 促凝剂微粒，导致血栓放大。纤溶酶原激活物抑制物-1(PAI-1)是 血浆中纤溶酶原激活物的主要抑制物。它以活性形式从肝脏分泌， 通过与Vitronectin结合来稳定内皮细胞。它使两种组织纤溶酶原激活物失活 (TPA)和尿激酶型纤溶酶原激活物(UPA)。PAI-1水平因高脂血症而升高，并且 PAI-1的升高似乎与因子V Leiden遗传异常协同作用，Leiden因子是一种亲血栓突变 因子V(莱顿)，使其对蛋白质降解具有抵抗性。PAI-1升高是可能的 可抑制纤溶，增加血栓形成。纤溶酶原激活物-1水平升高对血管紧张素转换酶的影响 静脉血栓形成一直是相互矛盾的。本提案的目的是确定PAI-1的作用 在小鼠完全下腔静脉结扎静脉血栓形成模型(Aim 1a)和一只小鼠的静脉血栓形成中的作用 下腔静脉狭窄诱导的静脉血栓形成模型(AIM 1b)。PAI-1缺失和PAI-1过表达小鼠 将被研究，以及玻璃体凝集素缺乏的小鼠，PAI-1/玻璃体凝集素联合缺乏的小鼠， 和野生型小鼠。我们还将使用药理学的PAI-1抑制。血栓形成、静脉壁/血栓 炎症、促凝剂微粒的产生和血栓/静脉壁纤维化 已评估。此外，我们还将确定血栓形成后抑制PAI-1的有效性，以及PAI-1的作用 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(目标1c)。最后，我们会 研究因子V Leiden杂合子和纯合子小鼠、ApoE高脂血症小鼠、 EGR-1缺失的小鼠(PAI-1启动子区域的Egr-1位点是由低氧诱导的，这是静脉的特征 停滞)和野生型小鼠(目标2a、2b)。这些水平的PAI-1将与 血栓形成。这一建议的结果应该更好地确定PAI-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.