Role of PAI-1 in Venous Thrombosis

PAI-1 在静脉血栓形成中的作用

• 批准号: 8150063
• 负责人: THOMAS William WAKEFIELD
• 金额: $ 23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150063
• 关键词: Adipose tissue; Affect; Alteplase; American; Apolipoprotein E; Binding; Characteristics; Deep Vein Thrombosis; Development; Endothelial Cells; Evaluation; Factor V Leiden mutation; Fibrinolysis; Fibrosis; Generations; Healthcare; Hyperlipidemia; Hypoxia; Inflammation; Inflammatory Response; Injury; Knockout Mice; Ligation; Liver; Mediating; Mediation; Modeling; Molecular Abnormality; Morbidity - disease rate; Mus; Plasma; Plasmin; Plasminogen Activator; Plasminogen Inactivators; Play; Production; Promoter Regions; Pulmonary Embolism; Resolution; Role; Site; Stenosis; Testing; Thrombin; Thromboembolism; Thrombophilia; Thrombosis; Thrombus; Time; Urokinase; Veins; Venous; Venous Thrombosis; Vitronectin; Wild Type Mouse; factor V Leiden; malignant breast neoplasm; mortality; overexpression; research study; response

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.

静脉血栓栓塞 (DVT/PE) 是一个重大的医疗保健问题，导致严重的发病率和 死亡。根据美国心脏协会 (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) 等 比乳腺癌和艾滋病的总和还要多。我们和其他人已经证明，显着的炎症 反应随静脉血栓栓塞发生，并且这种炎症通过产生 促凝微粒，导致血栓放大。纤溶酶原激活剂抑制剂-1 (PAI-1) 是 血浆中纤溶酶原激活剂的主要抑制剂。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。它使组织纤溶酶原激活剂失活 (tPA) 和尿激酶型纤溶酶原激活剂 (uPA)。 PAI-1 水平因高脂血症而升高，并且 PAI-1 升高似乎与因子 V Leiden 基因异常（一种血栓形成突变）具有协同作用。 因子 V (Leiden) 使其能够抵抗蛋白水解降解。 PAI-1 升高似乎是合理的 能抑制纤维蛋白溶解，增加血栓形成。 PAI-1水平升高的作用研究 静脉血栓形成是矛盾的。该提案的目的是确定PAI-1的作用 小鼠完整 IVC 结扎静脉血栓形成模型（目标 1a）和小鼠的静脉血栓形成 IVC 狭窄诱发的静脉血栓形成模型（目标 1b）。 PAI-1 缺失和 PAI-1 过表达的小鼠 将进行研究，以及玻连蛋白缺陷小鼠、PAI-1/玻连蛋白联合缺陷小鼠、 和野生型小鼠。我们还将使用药物 PAI-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 评价。此外，我们将确定血栓形成后 PAI-1 抑制的功效、 两种模型中纤溶酶的生成以及凝血酶在静脉血栓形成中的作用（目标 1c）。最后，我们将 研究 V 因子 Leiden 杂合子和纯合子小鼠、ApoE 高脂血症小鼠、 Egr-1缺失小鼠（PAI-1启动子区的Egr-1位点是由缺氧诱导的，缺氧是静脉 停滞）和两种模型中的野生型小鼠（目标 2a、2b）。 PAI-1 的这些水平将与 血栓形成。该提案的结果应该更好地定义 PAI-1 在静脉血栓形成中的作用。