title: Nonsteroidal anti-inflammatory drugs in-vitro and in-vivo treatment and Multidrug Resistance Protein 4 expression in human platelets.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Roma 00161, Italy. Electronic address: flavia.temperilli@uniroma1.it.
authors.forename: Flavia
authors.initials: F
authors.lastname: Temperilli
authors.affiliation: Department of Internal Medicine and Medical Specialities, Rheumatology Unit, Sapienza University of Rome, Viale del Policlinico 155, Roma 00161, Italy. Electronic address: manuela.difranco@uniroma1.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Di Franco
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Roma 00161, Italy. Electronic address: isabella.massimi@uniroma1.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Massimi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Roma 00161, Italy. Electronic address: marialuisa.guarino@uniroma1.it.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Guarino
authors.affiliation: Department of Internal Medicine and Medical Specialities, Rheumatology Unit, Sapienza University of Rome, Viale del Policlinico 155, Roma 00161, Italy. Electronic address: mariapaola.guzzo@uniroma1.it.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Guzzo
authors.affiliation: Department of Internal Medicine and Medical Specialities, Rheumatology Unit, Sapienza University of Rome, Viale del Policlinico 155, Roma 00161, Italy. Electronic address: guido.valesini@uniroma1.it.
authors.forename: Guido
authors.initials: G
authors.lastname: Valesini
authors.affiliation: I.R.C.C.S Neuromed, Località Camerelle, Pozzilli (CB) 86077, Italy. Electronic address: luigi.frati@uniroma1.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Roma 00161, Italy.
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Pulcinelli
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D016022:Case-Control Studies; D000068579:Celecoxib / Q000494:pharmacology; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D005260:Female; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009288:Naproxen / Q000494:pharmacology; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009288:Naproxen; D012333:RNA, Messenger; C073492:ABCC4 protein, human
keywords: MRP4; NSAID; Osteoarthritis; Platelets