Xinwei Shi , Yizhou Yang , Yue Gao , Chao Yuan , Xianqun Rao , Wei Li , Liting Wu , Tingting Yu , Ming Xu , Baoli Zhu , Lei Han , Kai Sun
{"title":"FTO通过m6A去甲基化修饰调控肺动脉平滑肌细胞的增殖和凋亡。","authors":"Xinwei Shi , Yizhou Yang , Yue Gao , Chao Yuan , Xianqun Rao , Wei Li , Liting Wu , Tingting Yu , Ming Xu , Baoli Zhu , Lei Han , Kai Sun","doi":"10.1016/j.pupt.2025.102382","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>To investigate whether FTO-mediated N6-methyladenosine (m6A) demethylation affects the proliferative/apoptotic phenotype of mouse pulmonary artery smooth muscle cells (PASMCs).</div></div><div><h3>Methods</h3><div>The hypoxia model of PASMCs was established to examine changes in FTO protein expression and m6A modification levels. Cell transfection, m6A expression profiling, mRNA stability testing, and protein-RNA binding assays were used to explore the effects of FTO and its downstream target, <em>CACNA1d</em>, on PASMC proliferation and apoptosis.</div></div><div><h3>Results</h3><div>Hypoxia downregulated FTO expression and upregulated m6A modification, leading to enhanced proliferation and reduced apoptosis in PASMCs. Overexpression of FTO reversed these effects, while FTO knockdown under normoxia mimicked the hypoxia-induced \"pro-proliferative and anti-apoptotic\" changes. Genome-wide m6A profiling identified <em>CACNA1d</em> as a potential downstream target of FTO, with YTHDC1 acting as the m6A reader. FTO binds <em>CACNA1d</em> mRNA and reduces its stability via m6A demethylation. CACNA1d knockdown partially mitigated the hypoxia-induced changes in PASMC proliferation and apoptosis. In addition, when the hypoxic culture was returned to normoxic culture, the level of apoptosis in PASMCs was restored to the pre-hypoxic level, and this was still observed after the overexpression of FTO or knockdown of CACNA1d expression.</div></div><div><h3>Conclusion</h3><div>FTO downregulation in hypoxic PASMCs increases m6A modification, promoting proliferation and inhibiting apoptosis by enhancing CACNA1d expression.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102382"},"PeriodicalIF":2.8000,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"FTO regulates the proliferation and apoptosis of pulmonary artery smooth muscle cells through m6A demethylation modification\",\"authors\":\"Xinwei Shi , Yizhou Yang , Yue Gao , Chao Yuan , Xianqun Rao , Wei Li , Liting Wu , Tingting Yu , Ming Xu , Baoli Zhu , Lei Han , Kai Sun\",\"doi\":\"10.1016/j.pupt.2025.102382\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>To investigate whether FTO-mediated N6-methyladenosine (m6A) demethylation affects the proliferative/apoptotic phenotype of mouse pulmonary artery smooth muscle cells (PASMCs).</div></div><div><h3>Methods</h3><div>The hypoxia model of PASMCs was established to examine changes in FTO protein expression and m6A modification levels. Cell transfection, m6A expression profiling, mRNA stability testing, and protein-RNA binding assays were used to explore the effects of FTO and its downstream target, <em>CACNA1d</em>, on PASMC proliferation and apoptosis.</div></div><div><h3>Results</h3><div>Hypoxia downregulated FTO expression and upregulated m6A modification, leading to enhanced proliferation and reduced apoptosis in PASMCs. Overexpression of FTO reversed these effects, while FTO knockdown under normoxia mimicked the hypoxia-induced \\\"pro-proliferative and anti-apoptotic\\\" changes. Genome-wide m6A profiling identified <em>CACNA1d</em> as a potential downstream target of FTO, with YTHDC1 acting as the m6A reader. FTO binds <em>CACNA1d</em> mRNA and reduces its stability via m6A demethylation. CACNA1d knockdown partially mitigated the hypoxia-induced changes in PASMC proliferation and apoptosis. In addition, when the hypoxic culture was returned to normoxic culture, the level of apoptosis in PASMCs was restored to the pre-hypoxic level, and this was still observed after the overexpression of FTO or knockdown of CACNA1d expression.</div></div><div><h3>Conclusion</h3><div>FTO downregulation in hypoxic PASMCs increases m6A modification, promoting proliferation and inhibiting apoptosis by enhancing CACNA1d expression.</div></div>\",\"PeriodicalId\":20799,\"journal\":{\"name\":\"Pulmonary pharmacology & therapeutics\",\"volume\":\"90 \",\"pages\":\"Article 102382\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pulmonary pharmacology & therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1094553925000392\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pulmonary pharmacology & therapeutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1094553925000392","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
FTO regulates the proliferation and apoptosis of pulmonary artery smooth muscle cells through m6A demethylation modification
Background
To investigate whether FTO-mediated N6-methyladenosine (m6A) demethylation affects the proliferative/apoptotic phenotype of mouse pulmonary artery smooth muscle cells (PASMCs).
Methods
The hypoxia model of PASMCs was established to examine changes in FTO protein expression and m6A modification levels. Cell transfection, m6A expression profiling, mRNA stability testing, and protein-RNA binding assays were used to explore the effects of FTO and its downstream target, CACNA1d, on PASMC proliferation and apoptosis.
Results
Hypoxia downregulated FTO expression and upregulated m6A modification, leading to enhanced proliferation and reduced apoptosis in PASMCs. Overexpression of FTO reversed these effects, while FTO knockdown under normoxia mimicked the hypoxia-induced "pro-proliferative and anti-apoptotic" changes. Genome-wide m6A profiling identified CACNA1d as a potential downstream target of FTO, with YTHDC1 acting as the m6A reader. FTO binds CACNA1d mRNA and reduces its stability via m6A demethylation. CACNA1d knockdown partially mitigated the hypoxia-induced changes in PASMC proliferation and apoptosis. In addition, when the hypoxic culture was returned to normoxic culture, the level of apoptosis in PASMCs was restored to the pre-hypoxic level, and this was still observed after the overexpression of FTO or knockdown of CACNA1d expression.
Conclusion
FTO downregulation in hypoxic PASMCs increases m6A modification, promoting proliferation and inhibiting apoptosis by enhancing CACNA1d expression.
期刊介绍:
Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews.
Research Areas Include:
• All major diseases of the lung
• Physiology
• Pathology
• Drug delivery
• Metabolism
• Pulmonary Toxicology.