Decreased platelet miR-199a-5p level might lead to high on-clopidogrel platelet reactivity in patients with coronary artery disease
Creators: name: Hu, Xiaolei
name: Li, Mupeng
name: Li, He
name: Song, Peiyuan
name: Zhang, Yanjiao
name: Zhou, Gan
name: Tang, Jie
name: Peng, Liming
name: Ma, Qilin
name: Chen, Xiaoping
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Physiology
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology

description: Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment. Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy. Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway. This study aimed to investigate the association between platelet miRNA levels and clopidogrel efficacy. Here we recruited 508 CAD patients who underwent clopidogrel antiplatelet therapy and determined the platelet reactivity index (PRI) to evaluate antiplatelet reactivity responses to clopidogrel. Subsequently, 22 patients with extreme clopidogrel response were selected for platelet small RNA sequencing. Another 41 CAD patients taking clopidogrel were collected to verify the differentially expressed candidate miRNAs. We found the metabolic types of the CYP2C19 enzyme (based on <i>CYP2C19 * 2</i> and <i>* 3</i> polymorphisms) could significantly affect the PRI of CAD patients with or without percutaneous coronary intervention (PCI) in Chinese. A total of 43 miRNAs were differentially expressed in the platelets from the 22 extreme clopidogrel response samples, and 109 miRNAs were differentially expressed in the 13 CYP2C19 extensive metabolizers with extreme clopidogrel response. Platelet miR-199a-5p levels were correlated negatively with PRI after clopidogrel therapy. Studies in cultured cells revealed that miR-199a-5p inhibited the expression of VASP, a key effector protein downstream of the P2Y<sub>12</sub> receptor. In conclusion, we found the expression of VASP could be inhibited by miR-199a-5p, and decreased platelet miR-199a-5p was associated with high on-clopidogrel platelet reactivity in CAD patients. <b>What is the context?</b> ● Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment. ● Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy. ● Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway. <b>What is new?</b> ● We found that decreased platelet miR-199a-5p level was associated with high on-clopidogrel platelet reactivity. ● Overexpression of miR-199a-5p significantly down-regulated the expression of VASP protein in cultured cells. <b>What is the impact?</b> ● The current study provided new insights into the exploration of interindividual variability in clopidogrel response from the perspective of miR-199a-5p and VASP interaction.