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）是一个主要的医疗保健问题，引起显著的发病率和发病率