Thromboxane A Synthase: A New Target for the Treatment of Cardiovascular Diseases

Mesitskaya, D. F.; Сыркин, А. Л.; Аксенова, М. Г.; Zhang, Yong; Zamyatnin, Andrey A.; Kopylov, F. Yu.

doi:10.2174/1871525716666180724115132

Cited by 14 publications

(9 citation statements)

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“…6 Phospholipase A 2 group (PLA2G4A, PLA2G6, and PLA2G7) encodes enzymes that catalyze the hydrolysis of membrane phospholipid to release AA and produce lysophospholipid, which is associated with platelet activation, 7 neuroaxonal dystrophy, 8 and coronary heart disease. 9 Thromboxane A synthase 1 (TBXAS1) encodes thromboxane synthase (TXS), which catalyzes the conversion of PGH 2 to TXA 2 and plays a vital role in ischemia, 10 cardiovascular disease 11 and stroke. 12 Thromboxane B 2 (TXB 2 ) is a more stable metabolite of TXA 2 that causes platelet aggregation.…”

Section: Introductionmentioning

confidence: 99%

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

et al. 2019

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Aspirin has been widely used for the prevention of cardiovascular diseases, but its antiplatelet efficiency varies between individuals. The present study aimed to evaluate response to aspirin based on gene profiles as well as potential regulating pathways using human blood samples and cell lines. Platelet function in patients 50 years or older with coronary artery disease on 100 mg/day aspirin was measured by light transmission aggregometry (LTA) of arachidonic acid (AA)-induced platelet aggregation. The expression of eight candidate genes—PTGS1/COX1, PLA2G4A, PLA2G6, PLA2G7, TBXAS1, TBXA2R, PTGIR, and ITGA2B—and the ingredients involved in AA metabolism were analyzed. Our data showed that the expressions of thromboxane A synthase 1 (TBXAS1), thromboxane synthase (TXS), and thromboxane B2 (TXB2) were increased in the upper quartile of platelet aggregation (LTA-AA_Q4) group compared with the lower quartile of platelet aggregation (LTA-AA_Q1) group. Our bioinformatics analysis suggested that TBXAS1 was targeted by miR-34b-3p via binding to its 3′-UTR, which was subsequently verified experimentally. Although overexpression of miR-34b-3p exhibited no apparent effect on cell proliferation, inhibition of miR-34b-3p promoted megakaryocyte viability. Our data demonstrated that the expression of TBXAS1 was higher in the aspirin hyporesponsiveness group than that in the hyperresponsiveness group, suggesting that high expression of TBXAS1 may be associated with aspirin hyporesponsiveness. miR-34b-3p may regulate the platelet and aspirin response by suppressing TBXAS1 expression and megakaryocyte proliferation.

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Section: Introductionmentioning

confidence: 99%

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

et al. 2019

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“…We designed the primers for six genes of interest with one housekeeping gene based on the prior reports ( Giaccone et al, 2010 ; Trabzuni et al, 2012 ; Mesitskaya et al, 2018 ; Shim and Madsen, 2018 ; Gable et al, 2019 ; Cacabelos, 2020 ; Hochstetler et al, 2020 ). Human gene transcripts were searched using Ensembl database ( http://useast.ensembl.org/index.html ).…”

Section: Methodsmentioning

confidence: 99%

TRPV4 mRNA is elevated in the caudate nucleus with NPH but not in Alzheimer’s disease

et al. 2022

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Symptoms of normal pressure hydrocephalus (NPH) and Alzheimer’s disease (AD) are somewhat similar, and it is common to misdiagnose these two conditions. Although there are fluid markers detectable in humans with NPH and AD, determining which biomarker is optimal in representing genetic characteristics consistent throughout species is poorly understood. Here, we hypothesize that NPH can be differentiated from AD with mRNA biomarkers of unvaried proximity to telomeres. We examined human caudate nucleus tissue samples for the expression of transient receptor potential cation channel subfamily V member 4 (TRPV4) and amyloid precursor protein (APP). Using the genome data viewer, we analyzed the mutability of TRPV4 and other genes in mice, rats, and humans through matching nucleotides of six genes of interest and one house keeping gene with two factors associated with high mutation rate: 1) proximity to telomeres or 2) high adenine and thymine (A + T) content. We found that TRPV4 and microtubule associated protein tau (MAPT) mRNA were elevated in NPH. In AD, mRNA expression of TRPV4 was unaltered unlike APP and other genes. In mice, rats, and humans, the nucleotide size of TRPV4 did not vary, while in other genes, the sizes were inconsistent. Proximity to telomeres in TRPV4 was <50 Mb across species. Our analyses reveal that TRPV4 gene size and mutability are conserved across three species, suggesting that TRPV4 can be a potential link in the pathophysiology of chronic hydrocephalus in aged humans (>65 years) and laboratory rodents at comparable ages.

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“…However, TBXAS1 has been recently proposed as a potential drug target for CVD. 28 Network three is comprised of an interaction between VAV3-AS1 rs3747945 and NPAS3 rs8008403.…”

Section: Rf-ifrs Replicates Existing Gene Associations With Cvd and Imentioning

confidence: 99%

Genome Wide Epistasis Study of On-Statin Cardiovascular Events with Iterative Feature Reduction and Selection

Feroze

Nguyen

et al. 2020

Preprint

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Background Predicting risk for major adverse cardiovascular events (MACE) is an evidence-based practice that incorporates lifestyle, history, and other risk factors. Statins reduce risk for MACE by decreasing lipids, but it is difficult to stratify risk following initiation of a statin. Genetic risk determinants for on-statin MACE are low-effect size and impossible to generalize. Our objective was to determine high-level epistatic risk factors for on-statin MACE with GWAS-scale data. Methods Controlled-access data for 5,980 subjects taking a statin collected from Vanderbilt University Medical Center's BioVU were obtained from dbGaP. We used Random Forest Iterative Feature Reduction and Selection (RF-IFRS) to select highly informative genetic and environmental features from a GWAS-scale dataset of patients taking statin medications. Variant-pairs were distilled into overlapping networks and assembled into individual decision trees to provide an interpretable set of variants and associated risk. Results 1,718 cases who suffered MACE and 4,172 controls were obtained from dbGaP. Pathway analysis showed that variants in genes related to vasculogenesis (FDR=0.024), angiogenesis (FDR=0.019), and carotid artery disease (FDR=0.034) were related to risk for on-statin MACE. We identified six gene-variant networks that predicted odds of on-statin MACE. The most elevated risk was found in a small subset of patients carrying variants in COL4A2, TMEM178B, SZT2, and TBXAS1 (OR=4.53, p<0.001). Conclusions The RF-IFRS method is a viable method for interpreting complex "black-box" findings from machine-learning. In this study, it identified epistatic networks that could be applied to risk estimation for on-statin MACE. Further study will seek to replicate these findings in other populations.

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Thromboxane A Synthase: A New Target for the Treatment of Cardiovascular Diseases

Cited by 14 publications

References 0 publications

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

TRPV4 mRNA is elevated in the caudate nucleus with NPH but not in Alzheimer’s disease

Genome Wide Epistasis Study of On-Statin Cardiovascular Events with Iterative Feature Reduction and Selection

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