Association of polymorphisms in thromboxane A2 receptor and thromboxane A synthase 1 with cerebral infarction in a Korean population

Park, Sun Ah; Park, Byung Lae; Park, Jeong Ho; Lee, Tae Kyeong; Sung, Ki Hyuk; Lee, You Kyoung; Chang, Hun Soo; Park, Choon-Sik; Shin, Hyoung Doo

doi:10.5483/bmbrep.2009.42.4.200

Cited by 23 publications

(21 citation statements)

References 30 publications

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“…Serum levels of TXA 2 and thromboxane receptor expression are elevated in patients with several vascular and ischemic diseases [37], including cerebral ischemia [2,21,43,55]. In addition, a specific polymorphism in the TXA 2 synthase-1 gene has been reported in some patients with cerebral infarction [40]. TXA 2 is produced by brain tissues [9] and cerebral arteries, both in vitro [15] and in vivo [42], and the release of TXA 2 in cerebral arteries is 10-fold higher than in coronary, mesenteric, or saphenous arteries [48].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice

Drouin

Farhat

Bolduc

et al. 2011

Pflugers Arch - Eur J Physiol

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We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H 2 O 2 , leading to endothelium-dependent dilation. In contrast, thromboxane A 2 (TXA 2 ), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-H 2 O 2 pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) Correspondence to: Eric Thorin. Electronic supplementary material The online version of this article (doi:10.1007/s00424-011-0973-y) contains supplementary material, which is available to authorized users. Ethical standardsThe experiments comply with the current laws of Canada in which they were performed. Conflict of interest CIHR Author ManuscriptCIHR Author Manuscript CIHR Author ManuscriptTXA 2 contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX= LDLR −/− ; hApoB +/+ ) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H 2 O 2 production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-H 2 O 2 pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA 2 with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-H 2 O 2 pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA 2 synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA 2 production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA 2 on the control of cerebral tone and maintained eNOS function.

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Section: Introductionmentioning

confidence: 99%

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice

Drouin

Farhat

Bolduc

et al. 2011

Pflugers Arch - Eur J Physiol

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“…TXAS variants with decreased activity could affect targeted drug intervention, as individuals with lower baseline TXAS activity may get less benefit from selective TXAS inhibitors. Recent findings indicate that genetic variation in TXAS is associated with several pathologies, including non-fatal myocardial infarction [33], cerebral infarction [34], and breast cancer [35]. In addition, pharmacogenetic consequences of TXAS polymorphisms on aspirin sensitivity have been investigated in stroke [36] and asthma patients [37].…”

Section: Resultsmentioning

confidence: 99%

Functional analysis of human thromboxane synthase polymorphic variants

Chen

Poole

Ulrich

et al. 2012

Pharmacogenetics and Genomics

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Background Thromboxane A synthase (TXAS) metabolizes the cyclooxygenase product prostaglandin (PG) H2 into thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation. Non-synonymous polymorphisms in the TBXAS gene have the potential to alter TXAS activity and affect TXA2 generation. Objectives Assess the functional effects of genetic variants in the TXAS protein, including K258E, L357V, Q417E, E450K and T451N. Methods Wild-type TXAS and the variant proteins were expressed in a bacterial system and purified by affinity and hydroxyapatite chromatography. The two characteristic catalytic activities of TXAS were assayed in each of the purified recombinant proteins: isomerization of PGH2 to TXA2 and fragmentation of PGH2 to 12-hydroxyheptadecatrienoic acid and malondialdehyde. Results All of the variants exhibited both isomerization and fragmentation activities. The KM values of the variants ranged from 27–52 µM PGH2 (wild-type value: 32 µM PGH2); Vmax values of the variants ranged from 18–40 units/mg (wild-type value: 41 units/mg). The kinetic differences were largest for the L357V variant, whose Vmax / KM ratio was just 27% of the wild-type value. Conclusion The increased KM and decreased Vmax values observed with L357V suggest this variant may generate less TXA2 at the low levels of PGH2 expected in vivo, raising the possibility of attenuated signaling via the thromboxane pathway.

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“…In yet another study, three TBXA2R gene SNPs (rs3786989, rs11085026, rs4523) were evaluated in Korean population. Even though marginal associations could be drawn between TBXA2R rs4523 and TBXA2R and associated haplotype block with the occurrence of vascular events, no significant association was statistically established after multiple comparisons (Table 3) [81]. Taken together, we have evidence that TXA2R rs768963 was linked to developments of ischemic stroke in Chinese and Japanese cohorts which comprised of 407 and 194 patients, respectively.…”

Section: Other Platelet's Receptorsmentioning

confidence: 87%

“…The gene encoding TBXA2R is located on chromosome 19p13.3 and has five exons. Until now, a few poly morphisms linked to amplified risk of stroke development have been identified (Table 1 & 2) [80,81].…”

Section: Other Platelet's Receptorsmentioning

confidence: 99%

Common Genetic Variants in Platelet Surface Receptors and its Association with Ischemic Stroke

et al. 2016

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Ischemic stroke has been named one of the leading causes of death worldwide. Whereas numerous biological mechanisms and molecules were found to be associated with stroke, platelets are particularly contributive to its pathogenesis. Recent data indicate considerable variability in platelet phenotype which accounts for differences in platelet surface receptor function, count and reactivity. These features collectively influence both the events leading to a disease and effectiveness of antiplatelet therapies. Consequently, genetic variants predisposing to cerebrovascular diseases can be sequenced using a wide array of techniques and become a useful tool in clinical setting. In this review, we provide an outline of common platelet polymorphisms that impose risk on ischemic stroke development and should be evaluated as targets to improve treatment. As study results are often inconsistent, partly due to differences in demographic characteristics between study populations and the fact that the functional impact of these variants has been relatively small, we conclude that both rare, low-frequency and common variants might account for genetic contribution on abnormal platelet response to antiplatelet drugs.

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Association of polymorphisms in thromboxane A2 receptor and thromboxane A synthase 1 with cerebral infarction in a Korean population

Cited by 23 publications

References 30 publications

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice

Functional analysis of human thromboxane synthase polymorphic variants

Common Genetic Variants in Platelet Surface Receptors and its Association with Ischemic Stroke

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