Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity

• Published in: Thrombosis research Vol. 131; no. 6; pp. 508 - 513
• Main Authors: Shi, Rui, Ge, Lan, Zhou, Xin, Ji, Wen-Jie, Lu, Rui-Yi, Zhang, Ying-Ying, Zeng, Shan, Liu, Xing, Zhao, Ji-Hong, Zhang, Wen-Cheng, Jiang, Tie-Min, Li, Yu-Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.06.2013
• Subjects: Aged; Blood Platelets - drug effects; Blood Platelets - metabolism; Clopidogrel; Coronary Disease - drug therapy; Coronary Disease - genetics; Down-Regulation - drug effects; Female; Hematology, Oncology and Palliative Medicine; High on-treatment platelet reactivity; Humans; Male; MicroRNAs - genetics; Middle Aged; MiroRNAs; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Platelet function test; Platelet Function Tests; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Ticlopidine - therapeutic use; Vasodilator-stimulated phosphoprotein; miRNAs; PRI; LVEF; PPI; cGMP; cAMP; UA; ADP; Cr; MFI; RBC; DBP; ACEI; real time PCR; WBC; BMI; SBP; VASP; CCB; NSTE-ACS; PGE1; Ago; 3’UTR; Platelet function test; TB; Vasodilator-stimulated phosphoprotein; TC; ARB; TG; High on-treatment platelet reactivity; MiroRNAs; PAG; PCI; LDPs; Clopidogrel; CHD; microRNAs; red blood cells; vasodilator-stimulated phosphoprotein; systolic blood pressure; total cholesterol; left ventricular ejection fraction; percutaneous coronary intervention; diastolic blood pressure; prostaglandin E1; white blood cells; adenosine diphosphate; uric acid; argonaute; mean fluorescence intensity; body mass index; angiotensin-converting enzyme inhibitor; 3’untranslated region; cyclic guanosine monophosphate; total bilirubin; leukocyte-depleted platelets; platelet aggregation; proton pump inhibitors; platelet reactivity index; creatinine; angiotensin receptor blockers; calcium channel blockers; triglycerides; cyclic adenosine monophosphate; real time polymerase chain reaction; coronary heart disease; non-ST-segment elevation acute coronary syndrome
• ISSN: 0049-3848; 1879-2472; 1879-2472
• DOI: 10.1016/j.thromres.2013.02.015

We aimed to investigate the relationship between platelet microRNA (miR-223 and miR-96) expression and clopidogrel responsiveness in patients with coronary heart disease (CHD). A total of 33 consecutive non-diabetic CHD patients scheduled for percutaneous coronary intervention were enrolled. Platelet reactivity after clopidogrel loading dose (300mg) was determined by two methods [platelet reactivity index (PRI), measured by vasodilator-stimulated phosphoprotein (VASP) phosphorylation flow cytometry and ADP-induced platelet aggregation (PAG), measured by light transmission aggregometry]. Total platelet RNA was isolated from purified platelets (CD45 magnetic bead negative selection) to quantify miR-223 and miR-96 expression by real-time PCR. All subjects were dichotomized according to PRI medians (normal-responders: PRI<56.5%, n=17 and low-responders: PRI>56.5%, n=16) and PAG medians (normal-responders: PAG<43%, n=17 and low-responders: PAG>43%, n=16). Compared with PRI-determined normal-responders, miR-223 expression, but not miR-96, was significantly decreased in low-responders (P=0.037). No differential expression of miR-223 and miR-96 was observed via PAG determination between normal- and low-responders. In addition, miR-223 expression, but not miR96, was statistically correlated with PRI (Spearman r=−0.403, P=0.020). Stepwise binary logistic regression analysis revealed that among factors that potentially influence platelet reactivity (CYP2C19*2 loss-of-function genotypes, use of calcium channel blockers/proton-pump inhibitors, age, obesity, smoking and platelet microRNAs), decreased miR-223 expression was the only independent predictor associated with the presence of PRI-determined low responders to clopidogrel (OR 0.189, 95% CI 0.043 to 0.836, P=0.028). The present work identifies decreased platelet miR-223 expression as a novel mechanism involved in blunted platelet response to clopidogrel in a Chinese population.