MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Abstract

BackgroundA mechanism involved in high on‐aspirin treatment residual platelet reactivity is platelet multidrug resistance protein 4 (MRP4) overexpression. Aspirin enhances platelet MRP4 expression with a PPARα‐dependent mechanism and reduces miR‐21 expression that, in turn, downregulates PPARα expression.ObjectiveThe aim of our study was to verify the relationship between miR‐21 and MRP4‐PPARα levels induced by aspirin treatment.MethodsWe evaluated the changes in MRP4‐PPARα, mRNA, MRP4 protein, and miR‐21 expression induced by aspirin in: (i) in vitro–treated megakaryoblastic cell line (DAMI), (ii) primary megakaryocytes cultures and derived platelets, (iii) healthy volunteers’ platelets treated with aspirin, and (iv) aspirinated patients (aspirin‐treated patients) and in a control population (control).ResultsWe observed an aspirin‐induced reverse relationship between the expression of miR‐21 and PPARα‐MRP4. In DAMI cells the miR‐21 mimic transfection reduces PPARα and MRP4 expression, even if cells were treated with aspirin after transfection. MiR‐21 inhibitor transfection induces PPARα and MRP4 expression that are not enhanced by aspirin treatment. In human megakaryocytes, aspirin treatment lead to a miR‐21 downregulation and a MRP4 upregulation and this trend is confirmed in derived platelets. In aspirin‐treated volunteers, an inverse relationship between miR‐21 and MRP4 platelet expression was found after aspirin treatment. A similar negative relationship was found in aspirin‐treated patients vs the control population.ConclusionThe results reported in this study provide information that aspirin induces the modulation of platelet miR‐21 expression levels and this modulation can be responsible for MRP4 enhancement in circulating platelets.

Grape Seed Proanthocyanidin Extract And Antiplatelet drug (Clopidogrel) Alleviates Nonalcoholic Fatty Liver Disease Via Inhibition Of Hepatic Inflammation In Rats

“…These data are in line withAn et al (2018) who observed a significant decrease in IL-1β mRNA levels by clopidogrel treatment.Likewise,clopidogrel significantly decreased the hepatic expressions of TIMP1 and TGF-β1, compared toαnaphthylisothiocyanate (xenobiotic)-exposed protease activated receptor-4 in mice treated with vehicle (Joshi et al, 2016). Regarding PPARα, rarelydata linking PPARα with clopidogrel, but contrarily to the present study, Massimi et al (2018) showed that, cells treated with Aspirin, an anti-platelet drug, had up-regulated PPARα mRNA. Anti-platelet treatment by clopidogrel in NALFD ameliorated the hepatic inflammation (Sitia et al, 2013) and abolished vascular inflammatory responses and remodeling (An et al, 2018), as platelet granules contain a variety of factors including TGFβ that are secreted upon platelet activation (Denslow et al, 2017),and a linear correlation of plasma TIMP1 levels and platelet count has been observed by the lower circulating TIMP1 levels in patients on clopidogrel treatment (Nagy et al, 2016).…”

Aspirin-Dependent Effects on Purinergic P2Y1 Receptor Expression

“…[2][3][4][5][6] Studies have shown that chronic use of aspirin can enhance expression of several proteins that can potentially affect cardiovascular outcomes. 7,8 In particular, it has been demonstrated that aspirin modulates miRNAs 9,10 and gene expression, such as the nuclear receptor PPARα modulation resulting in an increase in platelet MRP4. 11 Importantly, increased expression of MRP4 in platelets contributes to HARPR.…”

Noncoding RNA Roles in Pharmacogenomic Responses to Aspirin: New Molecular Mechanisms for an Old Drug

“…Aspirin (50 μ mol/L) therapy in human megakaryocytes reduced miR-21 and upregulated MRP4. miR-21 inhibited MRP4 and PPAR α transcription, and aspirin prevented these events [ 74 ].…”