Clin Exp Pharmacol Physiol. 2026 Feb;53(2):e70110. doi: 10.1111/1440-1681.70110.
ABSTRACT
OBJECTIVE: Abdominal aortic aneurysm (AAA) refers to a disease where the abdominal aorta progressively dilates to 3.0 cm or more, making it prone to rupture. The etiologic and pathophysiological mechanisms underlying the formation and development of AAA are not yet fully understood. A preliminary investigation was conducted into the effects of Kruppel-like factor 5 (KLF5) regulation of the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (NRF2/HO-1) signalling pathway on ferroptosis in AAA vascular smooth muscle cells (VSMCs).
METHODS: ApoE-/- mice or primary VSMCs were induced with angiotensin II (Ang II). KLF5 overexpression was achieved through adenovirus injection in the mouse model, and ML385 (NFR2 inhibitor) was injected to explore the involvement of the NRF2/HO-1 pathway in KLF5-regulated ferroptosis, inflammation, phenotypic switching and calcium deposition. Ang II-treated VSMCs were transiently transfected to overexpress KLF5 and/or incubated with Erastin (ferroptosis inducer) or ML385. The abdominal aorta was sampled from AAA model mice, and VSMC supernatants were collected to perform functional assays.
RESULTS: KLF5 expression was downregulated in abdominal aorta tissues from AAA mice. KLF5 overexpression ameliorated inflammatory response by reducing phenotypic switching in VSMCs and inhibited ferroptosis and vascular calcification by reducing oxidative stress. Induction of ferroptosis partially reversed the ameliorative effect of KLF5 on vascular calcification in VSMCs. KLF5 exerted antioxidant effects by increasing NRF2 nuclear translocation and upregulating HO-1. Inhibition of the NRF2/HO-1 pathway partially reversed KLF5 regulation of phenotypic switching and vascular calcification in VSMCs.
CONCLUSION: KLF5 may exert a protective effect by inhibiting ferroptosis and calcium deposition in VSMCs in AAA through regulation of the NRF2/HO-1 signalling pathway.
PMID:41656496 | DOI:10.1111/1440-1681.70110