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Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis

Abstract

Smooth muscle cell (SMC) phenotypic switch from a quiescent ‘contractile’ phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bisN4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.

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Fig. 1: Ferroptotic stress correlates with the dedifferentiation of SMCs.
Fig. 2: Ferroptosis inhibitor ferrostatin-1 (Fer-1) suppresses phenotype switch in dedifferentiated SMCs.
Fig. 3: Overexpression of GPX4 restrains phenotype switch in dedifferentiated SMCs.
Fig. 4: Knockin of GPX4 protects against SMC phenotype switch and neointima formation in mice.
Fig. 5: Conditional SMC-specific gene delivery of GPX4 blocks SMC phenotype switch and retards neointima formation in mice.
Fig. 6: Transcriptomic study identifies a comprehensive inhibition on mitochondrial respiratory metabolism in neointimal tissue of GPX4-knockin mice.
Fig. 7: Inhibition of ferroptotic stress corrects mitochondrial ROS generation, dysregulated mitochondrial dynamics and mitochondrial hyperpolarization in dedifferentiated SMCs.
Fig. 8: CuATSM prevents SMC phenotype switch, neointimal hyperplasia and vascular inflammation by inhibiting ferroptotic stress in mice.

Data availability

All data associated with this study are present in the paper or the Supplementary Materials. GO functional enrichment and KEGG pathway analysis were carried out by Goatools (https://github.com/tanghaibao/Goatools) and KOBAS (http://kobas.cbi.pku.edu.cn/home.do). The Raw data of RNA-sequencing was deposited in NCBI Sequence Read Archive (SRA) database (No. PRJNA839930).

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Funding

This work was supported by the grants from National Natural Science Foundation of China (91849135, 82073915, 81673485, 81773719, 81973312 and 81971306), the National Key Research and Development Project (2018YFA0108301), Shanghai Science and Technology Commission (21XD1424900, 19140904700, 19140904900, 2019CXJQ03 and 21S11901200), Shanghai Shuguang Program (19SG32), Shanghai “Rising Stars of Medical Talent” Youth Development Program-Youth Medical Talents-Clinical Pharmacist Program [SHWRS(2020)_087], and Tongji University-Fundamental Research Funds for the Central Universities (22120210560).

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PW and DJL conceived and designed research; QXJ, FYZ, JZ, XJW, ZZ, GYZ, JT, DYS and JBZ performed experiments; JZ provided patents samples; QXJ, FYZ, XJW, FMS and PW analyzed data. QXJ, PW and DJL wrote the manuscript. PW, DJL and FMS provided funding. All authors contributed with productive discussions and knowledge to the final version of this manuscript.

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Correspondence to Dong-Jie Li or Pei Wang.

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All studies related to human patients were approved by the Ethics Committee of Shanghai Tenth People’s Hospital (No. SHSY-IEC-KY-4.0/18-182/01). All animal-related procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Naval Medical University.

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Ji, QX., Zeng, FY., Zhou, J. et al. Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01099-5

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