MiR-1909-5p targeting GPX4 affects the progression of aortic dissection by modulating nicotine-induced ferroptosis

• Published in: Food and chemical toxicology 2024-09, Vol.191, p.114826, Article 114826
• Main Authors: Tao, Yan, Li, Gang, Wang, Zhibin, Wang, Shizhong, Peng, Xingang, Tang, Guozhang, Li, Xiaolu, Liu, Jianhua, Yu, Tao, Fu, Xiuxiu
• Format: Article
• Language: English
• Subjects: Animals; Aortic dissection; Aortic Dissection - chemically induced; Aortic Dissection - genetics; Aortic Dissection - metabolism; Disease Progression; Endothelial cells; Female; Ferroptosis - drug effects; GPX4; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR-1909-5p; Nicotine; Nicotine - pharmacology; Nicotine - toxicity; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism
• ISSN: 0278-6915; 1873-6351; 1873-6351
• DOI: 10.1016/j.fct.2024.114826

Aortic dissection (AD) is a prevalent and acute clinical catastrophe characterized by abrupt manifestation, swift progression, and elevated fatality rates. Despite smoking being a significant risk factor for AD, the precise pathological process remains elusive. This investigation endeavors to explore the mechanisms by which smoking accelerates AD through ferroptosis induction. In this novel study, we detected considerable endothelial cell death by ferroptosis within the aortic inner lining of both human AD patients with a smoking history and murine AD models induced by β-aminopropionitrile, angiotensin II, and nicotine. Utilizing bioinformatic approaches, we identified microRNAs regulating the expression of the ferroptosis inhibitor Glutathione peroxidase 4 (GPX4). Nicotine's impact on ferroptosis was further assessed in human umbilical vein endothelial cells (HUVECs) through modulation of miR-1909-5p. Additionally, the therapeutic potential of miR-1909-5p antagomir was evaluated in vivo in nicotine-exposed AD mice. Our results indicate a predominance of ferroptosis over apoptosis, pyroptosis, and necroptosis in the aortas of AD patients who smoke. Nicotine exposure instigated ferroptosis in HUVECs, where the miR-1909-5p/GPX4 axis was implicated. Modulation of miR-1909-5p in these cells revealed its regulatory role over GPX4 levels and subsequent endothelial ferroptosis. In vivo, miR-1909-5p suppression reduced ferroptosis and mitigated AD progression in the murine model. Our data underscore the involvement of the miR-1909-5p/GPX4 axis in the pathogenesis of nicotine-induced endothelial ferroptosis in AD. miR-1909-5p regulates ferroptosis of endothelial cells via targeting GPX4, leading to alleviation of aortic dissection. [Display omitted]