Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment

Abstract

Platelet multidrug resistance protein4 (MRP4)-overexpression has a role in reducing aspirin action. Aspirin in vivo treatment enhances platelet MRP4 expression and MRP4 mediated transport inhibition reduces platelet function and delays thrombus formation. The aim of our work was to verify whether MRP4 expression is enhanced in platelets obtained from patients under chronic aspirin treatment and whether it correlates with residual platelet reactivity. We evaluated changes on mRNA and protein-MRP4 expression and platelet aggregation in four populations: healthy volunteers (HV), aspirin-free control population (CTR), patients who started the treatment less than one month ago (ASA<1 month patients) and aspirinated patients who started the treatment more than two months ago (ASA>2 months patients). In platelets obtained from ASA>2 months patients, it was found a statistically significant MRP4 enhancement of both mRNA and protein expression compared to HV, CTR and ASA<1 month patients. Platelets obtained from ASA>2 months patients that present high levels of platelet MRP4, have higher serum TxB levels and collagen-induced platelet aggregation compared to patient with low levels of MRP4 in platelets. In addition collagen induced platelet aggregation is higher in in vitro aspirinated platelets obtained from patients with high levels of MRP4 patients compared to those obtained from patients with low MRP4 levels. We can assert that, in patients under chronic aspirin treatment, platelets that present high MRP4 levels have an increase of residual platelet reactivity, which is due in part to incomplete COX-1 inhibition, and in part to COX-1-independent mechanism.

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

“…To investigate whether aspirin could regulate miR‐21 expression even after in vivo administration and to verify the correlation between MRP4 and miR‐21, we explored miR‐21 expression in platelets obtained from volunteers after aspirin treatment which have aspirin induced MRP4 over‐expression, as previously shown 6, 8…”

“…These volunteers were previously analyzed for MRP4 expression. 8 Volunteers are subjects obtained from our transfusion center who had no risk factors and had no taken any medications.…”

“…To investigate whether aspirin could regulate miR-21 expression even after in vivo administration and to verify the correlation between MRP4 and miR-21, we explored miR-21 expression in platelets obtained from volunteers after aspirin treatment which have aspirin induced MRP4 over-expression, as previously shown. 6,8 In 300 mg/d aspirin-treated volunteers that show MRP4 upregulation after 15 days of treatment, miR-21 expression is downregulated in a statistically significant manner after 7 and 15 days (inhibition: 45 ± 17% and 47 ± 19%, respectively) ( Figure 6A).…”

“…7 Aspirin MRP4-induced over-expression correlates with high onaspirin treatment residual platelet reactivity, that is due in part to incomplete COX-1 inhibition, and in part to COX-1-independent mechanisms. 8 The PLATO trial group recently suggested a phenomenon called platelet adaptome, that originating in megakaryocytes given their diversity and ability to respond at the molecular level to pharmacological inhibition. 9 Furthermore, Lan et al demonstrated that aspirin treatment resulted in a reduction of miR-21 transcription in colorectal cancer cells.…”

Ovarian Damages Produced by Aerosolized Fine Particulate Matter (PM2.5) Pollution in Mice

“…Reasons may be that aspirin is not only a very good anti-inflammatory agent but also has a strong antioxidant effect – the two main mechanisms for damage caused by PM 2.5 . In addition, aspirin is a drug with a history of more than two thousand years and has proved to have anti-inflammatory, anticancer,[47] anticoagulation,[48] and antirheumatic[49] effects. This study represents the first demonstration that aspirin can significantly reduce ovarian tissue damages caused by PM 2.5 .…”