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

Abstract

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.

Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis

“…In the study of ferroptosis-related differentially expressed genes of atherosclerosis, HMOX1 was found to be remarkably increased and its inhibitor protected HASMCs from erastin-induced ferroptosis (Wu et al 2022a ). Additionally, Zhang et al demonstrated that RAS-selective lethal 3 (RSL3), a ferroptosis activator, promoted VSMC phenotypic switching and aggravated neointimal hyperplasia in mice (Zhang et al 2022 ). Therefore, P300 regulated VSMC ferroptosis may participate in the development of degenerative vascular disease, and activation of P300 is expected to prevent and treat these related diseases.…”

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis

“…38 A previous study indicated that ferroptosis inducers caused phenotypic switching in VSMCs, prompting them to transform into a secretory phenotype and accelerating ligation-induced intimal hyperplasia in mice. 16 Similarly, we found that ST-3GAL5 deficiency promoted switching of VSMCs to the secretory phenotype (data not shown). Whether VSMC phenotype switching contributes to the action of GM3 in AAA remains to be clarified.…”

“…15 Moreover, ferroptosis promotes dedifferentiation and phenotypic switching of SMCs. 16,17 Nonetheless, to date, the association between AAA and ferroptosis has not been fully delineated. Potential effects of sphingolipids and related enzymes on ferroptosis have also been identified.…”

Mesenchymal stem cell-derived extracellular vesicles protect against abdominal aortic aneurysm formation by inhibiting NET-induced ferroptosis

“…In our previous study, we found that NETs contributed to AAA formation by promoting the synthetic and proinflammatory phenotype in SMCs 31 . Recently, SMC ferroptosis has been shown to be closely associated with various types of vascular diseases, such as vascular calcification, aortic dissection, and neointimal hyperplasia 32 – 34 . This study is the first to report that ferroptosis is a regulated cell death type in SMCs during AAA formation.…”