Thromboxane A₂ Receptor Polymorphism in Association with Cerebral Infarction and its Regulation on Platelet Function

E-ISSN： 1875-5739|12|1|15-24

ISSN： 1567-2026

Source： Current Neurovascular Research, Vol.12, Iss.1, 2015-02, pp. : 15-24

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Abstract

Binding of thromboxane A₂ (TXA₂) to its receptor TXA₂R modulatesthrombosis/hemostasis and plays a vital role in the pathogenesis of cerebral infarction (CI). In thisstudy, we investigated the relationship between TXA₂R polymorphisms and CI in Chinese Hanpopulation and the effect on platelet function by these polymorphisms. Polymerase chain reactionand ligase detection reaction (PCR-LDR) was performed in 230 CI patients and 143 healthy volunteers to examine foursingle nucleotide polymorphisms (SNPs) in human TXA₂R gene (C795T, T924C and G1686A in the exon region, andrs768963 in the promoter region). We found that rs768963 polymorphism was significantly more frequent in the CI groupthan in the non-CI group and the T-T-G-T haplotype of C795T-T924C-G1686A-rs768963 was significantly less frequentin the CI subjects (0.238 versus 0.339; OR 0.617 [95%CI 0.444-0.856]). In the meantime, we constructed wild-type andmutant (C795T, G910A and T924C) eukaryotic expression plasmids, and transfected these plasmids into humanembryonic kidney (HEK) 293T cells or Chinese hamster ovary (CHO) cells stably expressing human TXA₂R (GPb/a-CHO). C795T and T924C variants of TXA2R led to increased ligand binding-induced intracellular calcium influx andfibrinogen-integrin conjugation, while dominant negative mutant G910A abolished the signal enhancement. Togetherthese data show that TXA2R polymorphisms may affect platelet function and the risk of developing cerebral ischemia.