Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics.

Arteriosclerosis, Thrombosis, and Vascular Biology
Benjamin E TourdotMichael Holinstat

Abstract

Platelet activation after stimulation of PAR (protease-activated receptor) 4 is heightened in platelets from blacks compared with those from whites. The difference in PAR4 signaling by race is partially explained by a single-nucleotide variant in PAR4 encoding for either an alanine or threonine at amino acid 120 in the second transmembrane domain. The current study sought to determine whether the difference in PAR4 signaling by this PAR4 variant is because of biased Gq signaling and whether the difference in PAR4 activity results in resistance to traditional antiplatelet intervention. Membranes expressing human PAR4-120 variants were reconstituted with either Gq or G13 to determine the kinetics of G protein activation. The kinetics of Gq and G13 activation were both increased in membranes expressing PAR4-Thr120 compared with those expressing PAR4-Ala120. Further, inhibiting PAR4-mediated platelet activation by targeting COX (cyclooxygenase) and P2Y12 receptor was less effective in platelets from subjects expressing PAR4-Thr120 compared with PAR4-Ala120. Additionally, ex vivo thrombus formation in whole blood was evaluated at high shear to determine the relationship between PAR4 variant expression and response to antiplatelet dr...Continue Reading

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Citations

Sep 26, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Megan A Slack, Scott M Gordon
Dec 24, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Hong S LuAlan Daugherty
Jan 2, 2020·The Journal of Biological Chemistry·Pierre E ThibeaultRithwik Ramachandran
Apr 23, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Xian LiJeremy P Wood
May 23, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Kimio SatohHiroaki Shimokawa
Jan 29, 2020·Research and Practice in Thrombosis and Haemostasis·Ben DriverDianne E van der Wal
Nov 14, 2019·International Journal of Molecular Sciences·Simeng LiJustin R Hamilton
Oct 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jennifer YeungGregory G Tall
Nov 6, 2020·Blood·Michael Holinstat
Nov 8, 2020·Journal of Thrombosis and Thrombolysis·Margaret InfeldDeepak Voora
Nov 23, 2020·Journal of Thrombosis and Haemostasis : JTH·Adriana YamaguchiMichael Holinstat
Aug 28, 2020·Thrombosis Research·Xu Han, Marvin T Nieman

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Datasets Mentioned

BETA
GM105671
GM120110
GM0088242

Methods Mentioned

BETA
PCR
electrophoresis

Software Mentioned

Plavix
gnomAD
Slidebook
GraphPad
Prism

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