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METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients
Quandan Tan1, Le Yang1,2, Shanshan Yuan3
1Department of Neurology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
Background:
N6-methyladenosine (m6A) is the most frequently occurring interior modification in eukaryotic messenger RNA (mRNA), and abnormal mRNA modifications can affect many biological processes. However, m6A's effect on the metabolism of antiplatelet drugs for the prevention of ischemic stroke (IS) remains largely unclear.
Methods:
We analyzed the m6A enzymes and m6A 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 m6A methylation on the expression of the drug-metabolizing enzymes (CYP2C19 and CYP2C6v1) in CR and non-CR samples.
Results:
Methyltransferase-like 3 (METTL3), an m6A 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 m6A 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.
Insights
Methyltransferase-like 3 (METTL3) enhances clopidogrel resistance in ischemic stroke patients by reducing CYP2C19 expression via N6-methyladenosine (m6A) modification. This finding clarifies m6A
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- N6-methyladenosine (m6A) is a prevalent mRNA modification impacting biological processes.
- The role of m6A in antiplatelet drug metabolism for ischemic stroke (IS) prevention is not well understood.
Purpose of the Study:
- To investigate the impact of m6A methylation on clopidogrel metabolism and resistance in IS.
- To identify specific m6A enzymes involved in clopidogrel resistance.
Main Methods:
- Analysis of m6A enzymes and methylation in peripheral blood of IS patients with/without clopidogrel resistance (CR).
- Comparison of m6A methylation in rat models with/without CR.
- Assessment of m6A's effect on drug-metabolizing enzymes (CYP2C19, CYP2C6v1) expression.
Main Results:
- Methyltransferase-like 3 (METTL3) was highly expressed in CR patients and rat models.
- METTL3 targets CYP2C19/CYP2C6v1 mRNA via m6A, leading to their reduced expression.
- Reduced CYP2C19/CYP2C6v1 expression correlated with decreased clopidogrel metabolism and CR.
Conclusions:
- METTL3-mediated m6A methylation of CYP2C19 mRNA may exacerbate clopidogrel resistance in IS patients.
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