Nonsteroidal anti-inflammatory drugs in-vitro and in-vivo treatment and Multidrug Resistance Protein 4 expression in human platelets

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• 作者：Flavia Temperilli^a ; ^{flavia.temperilli@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Manuela Di Franco^b ; ^{manuela.difranco@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Isabella Massimi^a ; ^{isabella.massimi@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Maria Luisa Guarino^a ; ^{marialuisa.guarino@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Maria Paola Guzzo^b ; ^{mariapaola.guzzo@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Guido Valesini^b ; ^{guido.valesini@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Luigi Frati^c ; ^{luigi.frati@uniroma1.it" class="auth_mail" title="E-mail the corresponding author} ; Fabio M. Pulcinelli^a ;
• 关键词：Platelets ; MRP4 ; NSAID ; Osteoarthritis
• 刊名：Vascular Pharmacology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：76
• 期：Complete
• 页码：11-17
• 全文大小：778 K

文摘

Platelet Multidrug Resistance Protein 4 (MRP4)-overexpression has a role in reducing aspirin action in patients after by-pass surgery. Aspirin induces platelet MRP4 over-expression, through megakaryocytes genomic modulation.

Aim of our work was to verify whether other non-steroidal antiinflammatory drugs (NSAIDs) enhance platelet MRP4 expression and evaluate platelet function in patients who overexpressed MRP4.

We evaluated MRP4-mRNA in a human megakacaryoblastic cell line (DAMI), treated with both COX-2 inhibitor (celecoxib) and traditional NSAIDs (diclofenac and naproxen). Osteoarthritis patients, who reported to take NSAIDs twice a week for at least four continuous weeks and a control population, who didn't take any drugs during the previous month, were enrolled. We evaluated platelet MRP4 amount, by both mRNA levels and protein expression (Western-Blot) and ADP induced platelet aggregation.

DAMI cells treated with celecoxib, diclofenac, and naproxen showed a significant increase in MRP4-mRNA expression compared to the mock culture.

Osteoarthritis patient platelets presented a higher expression of MRP4 (both at mRNA and protein levels) and an increase in ADP-induced platelet aggregation compared to the control population.

NSAID treatment induced platelet MRP4 overexpression. Osteoarthritis patients, who overexpress MRP4, showed platelet hyper-reactivity.

These evidences could explain in part the increased cardiovascular risk present during NSAID treatment.