https://orcid.org/0000-0002-0261-3148
Key Points
MRP8/14 upregulates platelet MRP4 through platelet miR-21-5p decrease, leading to increased COX-1 and shorter duration of aspirin response
Higher circulating miR-21-5p and MRP8/14 identify patients with accelerated recovery of platelet COX-1 during the 10-24-hour dosing interval
Low-dose aspirin is a cornerstone of cardiovascular prevention in high-risk patients, inhibiting platelet cyclooxygenase (COX-1) and reducing thromboxane (TX) A2 production for 24 hours. However, the duration of this effect varies among individuals, and the role of inflammation and platelet microRNAs in this variability remains unclear. This study identifies a thromboinflammatory mechanism linked to shorter duration of TXB2 suppression during aspirin therapy. This mechanism involves: 1) elevated circulating myeloid‐related protein (MRP) 8/14, indicating systemic inflammation; 2) reduced platelet miR-21-5p and increased circulating miR-21-5p, suggesting altered microRNA regulation; 3) MRP8/14-driven upregulation of platelet multidrug resistance protein (MRP) 4; 4) enhanced COX-1 expression, resulting in increased TX production. Patients with accelerated COX-1 recovery had increased circulating MRP8/14 and platelet MRP4, directly related with serum TXB2 and platelet COX-1 mRNA/protein levels. In vitro, recombinant MRP8/14 upregulated MRP4 and COX-1 in platelets and DAMI, , a human megakaryoblastic cell line, and MRP4 inhibition prevented this effect. Additionally, these patients exhibited lower platelet miR-21-5p levels and higher circulating miR-21-5p, inversely and directly related, respectively, to MRP8/14, MRP4 and serum TXB2 slope. In DAMI cells, rMRP8/14 reduced platelet miR21-5p and increased circulating miR21-5p, effects prevented by MRP4 inhibition. During immune-inflammation, reflected by high circulating MRP8/14, once-daily aspirin may incompletely inhibit COX-1 due to miR-21-5p downregulation, higher megakaryocyte/platelet MRP4 expression, COX-1 upregulation driving platelet activation and circulating miR-21-5p release. Circulating MRP8/14 and miR-21-5p can serve as biomarkers for patients with shorter duration of aspirin effect over 24 hours and potential targets to optimize antiplatelet therapy for high-risk patients.
