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WTAP-mediated GPX4 m6A methylation triggers PASMCs ferroptosis and pulmonary vascular fibrosis in pulmonary artery hypertension
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  • Wei Xin,
  • Siyu He,
  • Yanling Du,
  • Yang Yu,
  • Xinyue Song,
  • junting zhang ,
  • Yuan Jiang,
  • Songyue Li,
  • Jingya Zhang,
  • daling zhu
Wei Xin
Harbin Medical University
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Siyu He
Harbin Medical University
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Yanling Du
First Affiliated Hospital of Harbin Medical University
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Yang Yu
Harbin Medical University
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Xinyue Song
Harbin Medical University
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junting zhang
Harbin Medical University
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Yuan Jiang
Harbin Medical University
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Songyue Li
Harbin Medical University
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Jingya Zhang
Harbin Medical University
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daling zhu
Harbin Medical University
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Abstract

Background and Purpose Ferroptosis is a new form of cell death discovered in recent years. PH is a pulmonary circulatory disease partially characterized by small pulmonary vessel remodeling and fibrosis. However, researchers have not clearly determined whether ferroptosis is involved in PH. Here, this study examined the role and regulatory mechanism of ferroptosis in PH and pulmonary fibrosis. Experimental Approach To evaluate the occurrence of ferroptosis in rat PH models and in hypoxic PASMCs, MDA, GSH and iron assay were performed. The therapeutic potential of ferroptosis inhibitor fer-1 was evaluated using echocardiography, hemodynamic analysis and ventricular weight measurement in rat PH models. Ferroptosis-related molecule was determined by western blotting and RT-PCR. Changes in autophagy and fibrosis were analyzed by western blotting analysis, RT-PCR and immunofluorescence. Key Results Ferroptosis was existence in vivo and vitro PH models. The fer-1 significantly improved the pathological symptoms of PH and inhibited the occurrence of pulmonary vascular fibrosis. GPX4 was significantly lower expression in PH models, and serves as a key driver of PH-related ferroptosis. A KEGG pathway analysis and RT-PCR detection revealed that GPX4 drives ferroptosis in an autophagy-dependent manner. The RIP experiment verified that WTAP bound to the GPX4 pre-mRNA, induced m6A methylation and promoted its pre-mRNA degradation, thereby reducing the expression of GPX4 in hypoxic PASMCs. Conclusion and Implications This study proposed ferroptosis as a novel form of cell death in PH, and revealed the regulatory mechanism of the ferroptosis in PH, which is based on GPX4 m6A methylation regulated by WTAP.

Peer review status:UNDER REVIEW

15 Jul 2021Submitted to British Journal of Pharmacology
22 Jul 2021Assigned to Editor
22 Jul 2021Submission Checks Completed
11 Aug 2021Reviewer(s) Assigned