<br>ALKBH5 在缺氧期间诱导成纤维细胞向肌成纤维细胞转化，以防止心肌梗死后心脏破裂,Journal of Advanced Research

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ALKBH5 在缺氧期间诱导成纤维细胞向肌成纤维细胞转化，以防止心肌梗死后心脏破裂
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2023-09-09 , DOI: 10.1016/j.jare.2023.09.004
Kun Yang ₁ , Yongchao Zhao ₂ , Jingjing Hu ₃ , Rifeng Gao ₄ , Jiaran Shi ₅ , Xiang Wei ₄ , Juntao Chen ₆ , Kai Hu ₁ , Aijun Sun ₇ , Junbo Ge ₈

Affiliation

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Guizhou Province, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, China.
The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, China.
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.

N6-甲基腺苷 (m6A) 甲基化对心血管疾病产生显着影响。 m6A 去甲基酶 AlkB 同源物 5 (ALKBH5) 作为 m6A“擦除器”，负责减少 m6A 修饰。然而，它在心肌梗塞后（MI）愈合过程中心脏成纤维细胞中的作用仍然难以捉摸。探讨 ALKBH5 在梗塞修复过程中对心脏成纤维细胞的影响。通过在整体 ALKBH5 敲除、ALKBH5 敲除和成纤维细胞特异性 ALKBH5 敲除小鼠中永久结扎左前降支来模拟 MI，以研究 ALKBH5 在 MI 后胶原修复过程中的功能。进行甲基化 RNA 免疫沉淀测序以探索潜在的 ALKBH5 靶点。在 MI 后早期和缺氧成纤维细胞中观察到 ALKBH5 表达的显着变化。全局 ALKBH5 敲入可减少 MI 后的梗塞面积并改善心脏功能。整体和成纤维细胞特异性 ALKBH5 敲除小鼠均表现出较低的存活率以及胶原蛋白修复不良、心脏功能受损和心脏破裂。 ALKBH5 和 ALKBH5 的缺失都会导致成纤维细胞活化受损和胶原蛋白沉积减少。此外，缺氧通过 HIF-1α 依赖性转录调节上调肌成纤维细胞中 ALKBH5 的表达，而 TGF-β1 或 Ang II 则没有。从机制上讲，ALKBH5 通过 m6A 去甲基化促进 mRNA 的稳定性和 mRNA 的降解。成纤维细胞特异性 ErbB4 过表达可改善因 ALKBH5 敲除而导致的成纤维细胞向肌成纤维细胞转化受损和 MI 后修复不良的情况。成纤维细胞 ALKBH5 通过 m6A 依赖性方式稳定 mRNA，积极调节 MI 后愈合。 ALKBH5/ErbB4 可能是 MI 后心脏破裂的潜在治疗靶点。

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ALKBH5 induces fibroblast-to-myofibroblast transformation during hypoxia to protect against cardiac rupture after myocardial infarction

N6-methyladenosine (m6A) methylation produces a marked effect on cardiovascular diseases. The m6A demethylase AlkB homolog 5 (ALKBH5), as an m6A “eraser”, is responsible for decreased m6A modification. However, its role in cardiac fibroblasts during the post-myocardial infarction (MI) healing process remains elusive. To investigate the effect of ALKBH5 in cardiac fibroblasts during infarct repair. MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Dramatic alterations in ALKBH5 expression were observed during the early stages post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and ameliorated cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both and ALKBH5 loss resulted in impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts by HIF-1α-dependent transcriptional regulation. Mechanistically, ALKBH5 promoted the stability of mRNA and the degradation of mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Fibroblast ALKBH5 positively regulates post-MI healing by stabilization of mRNA in an m6A-dependent manner. ALKBH5/ErbB4 might be potential therapeutic targets for post-MI cardiac rupture.

更新日期：2023-09-09

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