The management of thrombotic disorders relies on the pharmacological targeting of either platelets or clotting factors. Protein disulfide isomerase (PDI) is secreted by platelets and endothelial cells following activation and localizes to the membrane surface. Given the role of PDI in regulating both platelet accumulation and fibrin generation in vivo, we propose to evaluate PDI as an antithrombotic target. A high throughput compound screen recently identified quercetin-3-rutinoside and related flavonoids as potent inhibitors of PDI oxidoreductase activity in vitro and thrombosis formation in vivo in several animal models. Several large epidemiologic studies have shown that quercetin-rich diets reduce cardiovascular events in humans. Considering that quercetin is a widely available nutritional supplement, the goal of this project is to investigate the antithrombotic activity of quercetin in hypercoagulable conditions as a means of validating PDI as a pharmacologic target.
The specific aims of this project are (1) to evaluate pharmacokinetics and pharmacodynamics of quercetin or isoquercetin with ascorbic acid as well as to investigate whether quercetin is reduces d-dimer levels in thrombotic condition characterized by endothelial activation (i.e. antiphospholipid antibodies);(2) to determine if quercetin prevents thrombosis in patients with high circulating tissue factor (i.e. cancer patients);and lastly, (3) to investigate whether quercetin can prevent thrombotic complications in a disorder characterized by pathologic platelet activation (i.e. heparin induced thrombocytopenia with thrombosis). By investigating quercetin in these different hypercoagulable conditions, we aim to translate recent laboratory observations directly into later stage clinical trials.
Given that thrombosis remains the leading cause of mortality in the U.S., establishing a novel class of anticoagulants would have far reaching impact in the management of a large number of thrombotic conditions. This proposal represents the initial evaluation of quercetin as an inhibitor of PDI to prevent thrombosis in humans.
|Bowley, Sheryl R; Fang, Chao; Merrill-Skoloff, Glenn et al. (2017) Protein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation. Nat Commun 8:14151|
|Stopa, Jack D; Baker, Katherine M; Grover, Steven P et al. (2017) Kinetic-based trapping by intervening sequence variants of the active sites of protein-disulfide isomerase identifies platelet protein substrates. J Biol Chem 292:9063-9074|
|Stopa, Jack D; Neuberg, Donna; Puligandla, Maneka et al. (2017) Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight 2:e89373|
|Flaumenhaft, R (2016) Probing for thiol isomerase activity in thrombi. J Thromb Haemost 14:1067-9|
|Galinski, Christine N; Zwicker, Jeffrey I; Kennedy, Daniel R (2016) Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro. Thromb Res 137:169-73|
|Schulman, Sol; Bendapudi, Pavan; Sharda, Anish et al. (2016) Extracellular Thiol Isomerases and Their Role in Thrombus Formation. Antioxid Redox Signal 24:1-15|
|Flaumenhaft, Robert; Furie, Bruce (2016) Vascular thiol isomerases. Blood 128:893-901|
|Bekendam, Roelof H; Bendapudi, Pavan K; Lin, Lin et al. (2016) A substrate-driven allosteric switch that enhances PDI catalytic activity. Nat Commun 7:12579|
|Flaumenhaft, Robert; Furie, Bruce; Zwicker, Jeffrey I (2015) Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease. Arterioscler Thromb Vasc Biol 35:16-23|
|Sharda, Anish; Kim, Sarah H; Jasuja, Reema et al. (2015) Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome. Blood 125:1633-42|
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