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

Objective: 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.

Methodology: 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.

Findings: 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.

Conclusions: Our data underscore the involvement of the miR-1909-5p/GPX4 axis in the pathogenesis of nicotine-induced endothelial Ferroptosis in AD.