Venous thromboembolism (DVT/PE) is a major healthcare problem causing significant morbidity andmortality. According to the AHA, up to two million Americans are affected annually by deep venousthrombosis (DVT) and 200,000 die annually from one of its complications, pulmonary embolism (PE), morethan breast cancer and AIDs combined. We and others have demonstrated that a significant inflammatoryresponse occurs with venous thromboembolism and that this inflammation, through the production ofprocoagulant microparticles, leads to thrombus amplification. Plasminogen Activator lnhibitor-1 (PAI-1) isthe primary inhibitor of plasminogen activators in plasma. It is secreted in an active form from liver andendothelial 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, andPAI-1 elevation appears to synergize with Factor V Leiden genetic abnormalities, a thrombophilic mutation ofFactor V (Leiden) which renders it resistent to proteolytic degradation. It is plausible that elevated PAI-1could suppress fibrinolysis and increase thrombosis. Studies on the role of elevated levels of PAI-1 tovenous thrombosis have been contradictory. The purpose of this proposal is to determine the role of PAI-1in venous thrombogenesis in a murine complete IVC ligtion venous thrombosis model (aim 1a) and a murineIVC stenosis-induced venous thrombosis model (aim 1b). Mice with PAI-1 deletion and PAI-1 overexpressionwill 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/thrombusinflammation, the production of procoagulant microparticles, and thrombus/vein wall fibrosis will beevaluated. Additionally, we will determine the efficacy of PAI-1 inhibition after thrombogenesis, the roles ofplasmin generation, and the role of thrombin in venous thrombosis in both models (aim 1c). Finally, we willstudy 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 venousstasis), and wild type mice in both models (aims 2a, 2b). These levels of PAI-1 will be correlated tothrombosis. The results of this proposal should better define the role of PAI-1 in venous thrombogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL089407-01A1
Application #
7485901
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2008-04-28
Project End
2013-03-31
Budget Start
2008-04-28
Budget End
2009-03-31
Support Year
1
Fiscal Year
2008
Total Cost
$387,343
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Obi, Andrea T; Andraska, Elizabeth; Kanthi, Yogendra et al. (2017) Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia. Thromb Haemost 117:339-348
Obi, Andrea T; Andraska, Elizabeth; Kanthi, Yogendra et al. (2016) Gram-Negative Pneumonia Alters Large-Vein Cell-Adhesion Molecule Profile and Potentiates Experimental Stasis Venous Thrombosis. J Vasc Res 53:186-195
Wu, Jianbo; Strawn, Tammy L; Luo, Mao et al. (2015) Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-?V?3 integrin cross talk. Arterioscler Thromb Vasc Biol 35:111-20
Obi, A T; Diaz, J A; Ballard-Lipka, N L et al. (2014) Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism. J Thromb Haemost 12:1353-63
Obi, Andrea T; Diaz, Jose A; Ballard-Lipka, Nicole L et al. (2014) Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner. J Vasc Surg Venous Lymphat Disord 2:441-450.e1
Li, Shih-Hon; Reinke, Ashley A; Sanders, Karen L et al. (2013) Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1. Proc Natl Acad Sci U S A 110:E4941-9
Diaz, Jose A; Alvarado, Christine M; Wrobleski, Shirley K et al. (2013) The electrolytic inferior vena cava model (EIM) to study thrombogenesis and thrombus resolution with continuous blood flow in the mouse. Thromb Haemost 109:1158-69
Patterson, K A; Zhang, X; Wrobleski, S K et al. (2013) Rosuvastatin reduced deep vein thrombosis in ApoE gene deleted mice with hyperlipidemia through non-lipid lowering effects. Thromb Res 131:268-76
Shuster, Katherine A; Wrobleski, Shirley K; Hawley, Angela E et al. (2013) Prothrombotic effects of thrombolytic therapy in a rat (Rattus norvegicus) model of venous thrombolysis. Comp Med 63:244-51
Diaz, Jose A; Obi, Andrea T; Myers Jr, Daniel D et al. (2012) Critical review of mouse models of venous thrombosis. Arterioscler Thromb Vasc Biol 32:556-62

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