2. Academic Validation
  3. Nicotine induces m6A-modified eNOS dysregulation to aggravate endothelial injury in male mice

Nicotine induces m6A-modified eNOS dysregulation to aggravate endothelial injury in male mice

  • Atherosclerosis. 2025 Dec:411:120558. doi: 10.1016/j.atherosclerosis.2025.120558.
Guoxia Shi 1,  Ziquan Jiang 1,  Zhuo Du 1,  Sibo Sun 1,  Dongxu Huang 1,  Pingping Wan 1,  Shuang Li 1,  Manyu Du 1,  Qiuying Yan 1,  Bo Yu 2,  Caiying Tang 1,  Ping Sun 3,  Jiannan Dai 4
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department 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; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, Heilongjiang Province, China.
  • 3 The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 4 Department 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; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, Heilongjiang Province, China. Electronic address: [email protected].
PMID: 41192190 DOI: 10.1016/j.atherosclerosis.2025.120558
Abstract

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.

Keywords

Nicotine; Vascular endothelial injury; eNOS; m6A modification.

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