title: Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  A total of 33 consecutive non-diabetic CHD patients scheduled for percutaneous coronary intervention were enrolled. Platelet reactivity after clopidogrel loading dose (300 mg) 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  The present work identifies decreased platelet miR-223 expression as a novel mechanism involved in blunted platelet response to clopidogrel in a Chinese population.
authors.affiliation: Institute of Cardiovascular Disease and Heart Center, Pingjin Hospital, Logistics University of the Chinese People's Armed Police Forces, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
authors.forename: Lan
authors.initials: L
authors.lastname: Ge
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Ji
authors.forename: Rui-Yi
authors.initials: RY
authors.lastname: Lu
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Zhao
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Zhang
authors.forename: Tie-Min
authors.initials: TM
authors.lastname: Jiang
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Li
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003327:Coronary Disease / Q000188:drug therapy* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010979:Platelet Function Tests; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000077144:Clopidogrel; D035683:MicroRNAs; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine; C525067:MIR223, human; C541492:MIRN96 microRNA, human