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Published on: March 3, 2023
Nicotine induces m6A-modified eNOS dysregulation to aggravate endothelial injury in male mice
Guoxia Shi1, Ziquan Jiang1, Zhuo Du1
1Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China.
Background And Aims:
Cigarette smoking is a well-established risk factor for vascular injury. However, the effects of nicotine alone remain poorly understood. This study aimed to investigate whether nicotine regulates endothelial nitric oxide synthase (eNOS) expression, thereby contributing to vascular endothelial injury, and to elucidate the critical involvement of N6-Methyladenosine (m6A) modification in this process.
Methods:
Mice were exposed to 12 weeks of nicotine exposure, to examine its impact on vascular endothelial injury. Human coronary artery endothelial cells were stimulated with nicotine in vitro, and qRT-PCR and MeRIP-qPCR were performed to measure eNOS expression and its m6A modification levels, respectively. RNA pull-down assays were used to identify eNOS mRNA-interacting proteins, and an endothelial-specific methyltransferase-like protein 3 (Mettl3) knockout model and eNOS recombinant adenovirus were utilized to validate the role of eNOS m6A modification in nicotine-induced endothelial injury.
Results:
Nicotine stimulation induced vascular endothelial injury by activating endothelial cells, thereby increasing their permeability and migration capacity through suppressing eNOS expression. These pathological changes were alleviated in both eNOS-overexpressing and endothelial-specific Mettl3 knockout mice. Mechanistically, nicotine increased the m6A modification of eNOS through METTL3. METTL3 then interacted with the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which led to mRNA degradation and reduced protein levels via the m6A-dependent pathway.
Conclusions:
We propose a novel mechanism by which nicotine promotes vascular endothelial injury via METTL3/YTHDF2-mediated m6A modification of eNOS in endothelial cells. This study offers a new insights for the formation of vascular endothelial injury.
