METTL3-mediated Methylation of CYP2C19 MRNA May Aggravate Clopidogrel Resistance in Ischemic Stroke Patients

Overview

Journal Open Med (Wars)

Specialty General Medicine

Date 2024 Mar 11

PMID 38463525

Authors

Quandan Tan

Le Yang

Shanshan Yuan

Danni Zheng

Yapeng Lin

Kejie Chen

Ying He

Shuntian Chen

Junli Hao

Jin Dai

Song He

Fengkai Mao

Xinyi Leng

Haisong Jiang

Jie Yang

Affiliations

Soon will be listed here.

Abstract

Background: N6-methyladenosine (mA) is the most frequently occurring interior modification in eukaryotic messenger RNA (mRNA), and abnormal mRNA modifications can affect many biological processes. However, mA's effect on the metabolism of antiplatelet drugs for the prevention of ischemic stroke (IS) remains largely unclear.

Methods: We analyzed the mA enzymes and mA methylation in peripheral blood samples of IS patients with/without clopidogrel resistance (CR), and the peripheral blood and liver of rat models with/without CR. We also compared the effect of mA methylation on the expression of the drug-metabolizing enzymes (CYP2C19 and CYP2C6v1) in CR and non-CR samples.

Results: Methyltransferase-like 3 (METTL3), an mA enzyme, was highly expressed in the peripheral blood of patients with CR, and in both the peripheral blood and liver of rats with CR. This enzyme targets CYP2C19 or CYP2C6v1 mRNA through mA methylation, resulting in low expression of CYP2C19 or CYP2C6v1 mRNA. Consequently, this leads to decreased clopidogrel metabolism and CR.

Conclusion: The METTL3-mediated methylation of CYP2C19 mRNA may aggravate CR in IS patients.

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