Pharmacogenomics of anti-platelet therapy focused on peripheral blood cells of coronary arterial disease patients

Luchessi, André Ducati; Silbiger, Vivian N.; Hirata, Rosário Dominguez Crespo; Lima-Neto, Lidio Gonçalves; Cavichioli, Débora; Íñiguez, Andrés; Bravo, Marisol; Bastos, Guillermo; Sousa, Amanda G. M. R.; Brión, Marı́a; Carracedo, Ángel; Hirata, Mário Hiroyuki

doi:10.1016/j.cca.2013.06.021

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…In addition, catecholamines such as epinephrine can also act as platelet primers when used at suboptimal concentrations . Interestingly, recent pharmacogenomics studies have also linked increased expression of IGF‐1 and IGF‐1 receptor mRNA with ASA resistance . Furthermore, coronary heart disease (CHD) patients have been found to have significantly higher serum concentrations of IGF‐1, a feature that is believed to contribute to coronary atherosclerosis .…”

Section: Introductionmentioning

confidence: 99%

Circulating primers enhance platelet function and induce resistance to antiplatelet therapy

Blair

Moore

Hers

2015

Journal of Thrombosis and Haemostasis

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BackgroundAspirin and P2Y12 antagonists are antiplatelet compounds that are used clinically in patients with thrombosis. However, some patients are ‘resistant’ to antiplatelet therapy, which increases their risk of developing acute coronary syndromes. These patients often present with an underlying condition that is associated with altered levels of circulating platelet primers and platelet hyperactivity. Platelet primers cannot stimulate platelet activation, but, in combination with physiologic stimuli, significantly enhance platelet function.ObjectivesTo explore the role of platelet primers in resistance to antiplatelet therapy, and to evaluate whether phosphoinositide 3-kinase (PI3K) contributes to this process.Methods and ResultsWe used platelet aggregation, thromboxane A2 production and ex vivo thrombus formation as functional readouts of platelet activity. Platelets were treated with the potent P2Y12 inhibitor AR-C66096, aspirin, or a combination of both, in the presence or absence of the platelet primers insulin-like growth factor-1 (IGF-1) and thrombopoietin (TPO), or the Gz-coupled receptor ligand epinephrine. We found that platelet primers largely overcame the inhibitory effects of antiplatelet compounds on platelet functional responses. IGF-1-mediated and TPO-mediated, but not epinephrine-mediated, enhancements in the presence of antiplatelet drugs were blocked by the PI3K inhibitors wortmannin and LY294002.ConclusionsThese results demonstrate that platelet primers can contribute to antiplatelet resistance. Furthermore, our data demonstrate that there are PI3K-dependent and PI3K-independent mechanisms driving primer-mediated resistance to antiplatelet therapy.

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Section: Introductionmentioning

confidence: 99%

Circulating primers enhance platelet function and induce resistance to antiplatelet therapy

Blair

Moore

Hers

2015

Journal of Thrombosis and Haemostasis

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“…Therefore, ABCC3 mRNA expression may be useful for clopidogrel monitoring in ACS patients. We previously reported that ACS patients with elevated ABCC3 mRNA expression did not respond to clopidogrel therapy , supporting the relationship between high CAM concentrations and high platelet activity as well as increased ACS risk. However, we cannot rule out the influence of other therapies used in the treatment of ACS patients, including clopidogrel and ASA, on ABCC3 regulation in peripheral blood cells.…”

Section: Discussionmentioning

confidence: 52%

ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a Carboxylic Acid Metabolite in Patients on Clopidogrel and Aspirin Therapy

Luchessi

Concheiro

Germano

et al. 2017

Basic Clin Pharma Tox

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Acetylsalicylic acid (ASA) and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome (ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 (ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid (SA) and a carboxylic acid metabolite (CAM). Clopidogrel, CAM and SA plasma concentrations were measured simultaneously by liquid chromatography-tandem mass spectrometry (LCMS/MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392 and rs739923) and CYP2C19*2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression (r = 0.494, p < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers (p = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression (p = 0.017), rs757421 AA genotype (p = 0.001), blood collection time (p = 0.018) and clopidogrel dose (p = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19*2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel.

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“…Limma package () in R (version 3.5.1; ) was used to identify differentially expressed lncRNAs and mRNAs among the asthma and control groups via a t-test (18). Fold change (FC)>1.2 and P<0.05 were set as the criteria for differential expression (19). Hierarchical clustering was conducted in R scripts.…”

Section: Methodsmentioning

confidence: 99%

Integrative analysis of the contribution of mRNAs and long non‑coding RNAs to the pathogenesis of asthma

et al. 2019

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asthma, a common but poorly controlled disease, is one of the most serious health problems worldwide; however, the mechanisms underlying the development of asthma remain unknown. long non-coding rnas (lncrnas) and mrnas serve important roles in the initiation and progression of various diseases. The present study aimed to investigate the role of differentially expressed lncrnas and mrnas associated with asthma. differentially expressed lncrnas and mrnas were screened between the expression data of 62 patients with asthma and 43 healthy controls. Gene ontology (Go) and Kyoto encyclopedia of Genes and Genomes (KeGG) analyses were performed to investigate the biological functions and pathways associated with the lncrnas and mRNAs identified. Protein-protein interaction (PPI) networks were subsequently generated. in addition, lncrna-mrna weighted co-expression networks were obtained. in total, 159 differentially expressed lncrnas and 1,261 mrnas were identified. GO and KEGG analyses revealed that differentially expressed mrnas regulated asthma by participating in the 'vascular endothelial (VeGF) signaling pathway', 'oxidative phosphorylation', 'Fc ε ri signaling pathway', 'amino sugar and nucleotide sugar metabolism', 'histidine metabolism', 'β-alanine metabolism' and 'extracellular matrix-receptor interaction' (P<0.05). Furthermore, protein kinase B 1 had the highest connectivity degree in the PPi network, and was significantly enriched in the 'VEGF signaling pathway' and 'Fc ε ri signaling pathway'. a total of 8 lncrnas in the lncrna-mrna co-expression network were reported to interact with 52 differentially expressed genes, which were enriched in asthma-associated Go and KeGG pathways. The results obtained in the present study may provide insight into the profile of differentially expressed lncrnas associated with asthma. The identification of a cluster of dysregulated lncrnas and mrnas may serve as a potential therapeutic strategy to reverse the progression of asthma.

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Pharmacogenomics of anti-platelet therapy focused on peripheral blood cells of coronary arterial disease patients

Abstract: The variation in response to ASA may be related with an increased expression of IGF1 and IGF1R, as well as a response to clopidogrel can be affected by pharmacokinetic change related to the reverse transport pathway by increased expression of ABCC3.

Cited by 8 publications

References 44 publications

Circulating primers enhance platelet function and induce resistance to antiplatelet therapy

Circulating primers enhance platelet function and induce resistance to antiplatelet therapy

ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a Carboxylic Acid Metabolite in Patients on Clopidogrel and Aspirin Therapy

Integrative analysis of the contribution of mRNAs and long non‑coding RNAs to the pathogenesis of asthma

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