Blacks are at an increased risk of myocardial infarction and stroke, two diseases with strong thrombotic components, compared to whites even after adjusting for socioeconomic and clinical confounders. Recent work in our group suggests that racial differences in the risk for a thrombotic event is at least in part due to geneic polymorphisms in the thrombin receptor, protease-activated receptor 4 (PAR4). Our preliminary data demonstrates that independent of race individuals homozygous for the T120 variant of PAR4 have an increase in PAR4-mediated platelet reactivity compared to individuals homozygous for the A120 variant. Additionally, this variant dependent activation of PAR4 persists in platelets treated ex vivo with COX and P2Y12 antagonists. To further delineate how the PAR4 variant influences platelet reactivity we propose to characterize the mechanism by which the T120A PAR4 variant increases PAR4-mediated platelet reactivity and determine if this variant alters platelet reactivity in the presence of current antiplatelet therapy. To this end, Ai 1 will address the mechanism by which the PAR4 T120 variant increases PAR4-mediated platelet reactivity by analyzing the biochemical components of the Gq and G12/13 pathways in PAR4 stimulated platelets isolated from donors expressing either variant. Additionally, it remains unknown if the PAR4 T120A substitution enhances PAR4-mediated platelet reactivity in platelets from cardiac patients on dual antiplatelet therapy. Hence, in Aim 2 we will recruit patients on dual antiplatelet that are homozygous for either variant to assess their platelet reactivity to determine if platelets isolated from individuals expressing T120 have an increase in PAR4-mediated platelet activation compared to platelets from individuals expressing A120. Finally, our preliminary data suggests that PAR4 is a new target for decreasing thrombotic events in patients with the T120 PAR4 variant. Therefore, in Aim 3 we will test the function of PAR4 antagonists to inhibit platelet activation of subjects independent of PAR4 variant. A further understanding of the mechanism by which the PAR4 variants enhance platelet reactivity will provide evidence for targeted therapy to treat those with an increase in PAR4 platelet reactivity.
A racial disparity exists between blacks and whites in the risk for a thrombotic event. This racial disparity is in part due to a polymorphism in the thrombin receptor, PAR4, more frequently expressed in blacks than whites. Determining the mechanism by which polymorphisms in PAR4 cause a difference in platelet reactivity will provide evidence for new therapeutic targets to reduce platelet reactivity in a large population expressing PAR4 polymorphisms.
| Tourdot, Benjamin E; Stoveken, Hannah; Trumbo, Derek et al. (2018) Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics. Arterioscler Thromb Vasc Biol 38:1632-1643 |
| Adili, Reheman; Tourdot, Benjamin E; Mast, Katherine et al. (2017) First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis. Arterioscler Thromb Vasc Biol 37:1828-1839 |
| Tourdot, Benjamin E; Adili, Reheman; Isingizwe, Zitha R et al. (2017) 12-HETrE inhibits platelet reactivity and thrombosis in part through the prostacyclin receptor. Blood Adv 1:1124-1131 |
| Yeung, Jennifer; Tourdot, Benjamin E; Adili, Reheman et al. (2016) 12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-?-Linolenic Acid, Inhibits Thrombosis via G?s Signaling in Platelets. Arterioscler Thromb Vasc Biol 36:2068-77 |
