Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice

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dc.contributor.authorZhang, Shunchi
dc.contributor.authorBei, Yanrou
dc.contributor.authorHuang, Yueling
dc.contributor.authorHuang, Yimin
dc.contributor.authorHou, Lianjie
dc.contributor.authorZheng, Xi-Long
dc.contributor.authorXu, Yiming
dc.contributor.authorWu, Shaoguo
dc.contributor.authorDai, Xiaoyan
dc.date.accessioned2022-10-09T00:05:28Z
dc.date.available2022-10-09T00:05:28Z
dc.date.issued2022-10-03
dc.date.updated2022-10-09T00:05:27Z
dc.description.abstractAbstract Background Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear. Methods The mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments. Results Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-l-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs. Conclusions Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.
dc.identifier.citationMolecular Medicine. 2022 Oct 03;28(1):121
dc.identifier.doihttps://doi.org/10.1186/s10020-022-00549-7
dc.identifier.urihttp://hdl.handle.net/1880/115357
dc.identifier.urihttps://doi.org/10.11575/PRISM/45132
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleInduction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice
dc.typeJournal Article
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