METTL3介导的CYP2C19 mRNA甲基化可能会加重缺血性中风患者对氯吡格雷的抵抗。
METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients.
作者信息
Tan Quandan, Yang Le, Yuan Shanshan, Zheng Danni, Lin Yapeng, Chen Kejie, He Ying, Chen Shuntian, Hao Junli, Dai Jin, He Song, Mao Fengkai, Leng Xinyi, Jiang Haisong, Yang Jie
机构信息
Department of Neurology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, Chengdu, China.
出版信息
Open Med (Wars). 2024 Feb 7;19(1):20240899. doi: 10.1515/med-2024-0899. eCollection 2024.
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.
背景
N6-甲基腺苷（mA）是真核生物信使核糖核酸（mRNA）中最常见的内部修饰，异常的mRNA修饰可影响许多生物学过程。然而，mA对用于预防缺血性中风（IS）的抗血小板药物代谢的影响仍不清楚。
方法
我们分析了有/无氯吡格雷抵抗（CR）的IS患者外周血样本以及有/无CR的大鼠模型的外周血和肝脏中的mA酶和mA甲基化情况。我们还比较了mA甲基化对CR和非CR样本中药物代谢酶（CYP2C19和CYP2C6v1）表达的影响。
结果
mA酶样甲基转移酶3（METTL3）在CR患者的外周血以及CR大鼠的外周血和肝脏中均高表达。该酶通过mA甲基化靶向CYP2C19或CYP2C6v1 mRNA，导致CYP2C19或CYP2C6v1 mRNA表达降低。因此，这导致氯吡格雷代谢减少和CR。
结论
METTL3介导的CYP2C19 mRNA甲基化可能会加重IS患者的CR。
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