Epitranscriptomic regulation of cardiac fibrosis via YTHDF1-dependent PIEZO2 mRNA m6A modification.

Autor:	Ding JF; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China., Tu B; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China., Song K; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China., Liu ZY; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China., Lin LC; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China., Liu ZY; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China., Shi Y; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China., Yang JJ; Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China., Zhao JY; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China., Tao H; Department of Cardiothoracic Surgery, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China.; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Nov 05. Date of Electronic Publication: 2024 Nov 05.
DOI:	10.1093/cvr/cvae239
Abstrakt:	Background: Mechanosensitive ion channels play a key role in heart development, physiology, and disease. However, little is known about the molecular mechanisms of the mechanosensitive nonselective cationic channel Piezo family in cardiac fibrosis. Methods and Results: Mice were treated with ISO/Ang-II/TAC to induce cardiac fibrosis. AAV9 carrying POSTN promoter-driven small hairpin RNA targeting YTHDF1, and Piezo2 were administered to ISO mice to investigate their roles in cardiac fibrosis. RNA-seq, single-cell sequencing, and histological and biochemical analyses were performed to determine the mechanism by which YTHDF1 regulates Piezo2 expression in cardiac fibrosis. Piezo2 was reconstituted in YTHDF1-deficient cardiac fibroblasts and mouse hearts to study its effects on cardiac fibroblast autophagy and fibrosis. Piezo2 but not Piezo1 expression increased in experimental cardiac fibrosis and TGF-β1-induced cardiac fibroblasts. Fibroblast-specific Piezo2 deficiency ameliorated fibroblast activation and autophagy and inhibited cardiac fibrosis. Mechanistically, Piezo2 upregulation was associated with elevated m6A mRNA levels. Site-specific m6A modifications at peak_26355 were crucial for regulating the binding of YTHDF1 to Piezo2 mRNA and inducing Piezo2 translation. Notably, Piezo2 epitranscriptomic repression ameliorated experimental cardiac fibrosis. Conclusions: We demonstrated a novel epitranscriptomic mechanism through which YTHDF1 recognizes Piezo2 and controls cardiac fibroblast autophagy and fibrosis through m6A-dependent modulation. Our findings provide new insights for the development of preventive measures for cardiac fibrosis. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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