Upregulation of eIF2α by m⁶A modification accelerates the proliferation of pulmonary artery smooth muscle cells in MCT-induced pulmonary arterial hypertension rats.

IF 2.4 3区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Journal of Cardiovascular Translational Research Pub Date : 2024-06-01 Epub Date: 2023-11-16 DOI:10.1007/s12265-023-10458-7

Jing Zhang, Wen-Qian Huang, Yu-Rong Zhang, Na Liang, Nan-Ping Li, Gang-Kai Tan, Shao-Xin Gong, Ai-Ping Wang

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Abstract

Pulmonary arterial hypertension (PAH) is a malignant cardiovascular disease. Eukaryotic initiation factor 2α (eIF2α) plays an important role in the proliferation of pulmonary artery smooth muscle cells (PASMCs) in hypoxia-induced pulmonary hypertension (HPH) rats. However, the regulatory mechanism of eIF2α remains poorly understood in PAH rats. Here, we discover eIF2α is markedly upregulated in monocrotaline (MCT)-induced PAH rats, eIF2α can be upregulated by mRNA methylation, and upregulated eIF2α can promote PASMC proliferation in MCT-PAH rats. GSK2606414, eIF2α inhibitor, can downregulate the expression of eIF2α and alleviate PASMC proliferation in MCT-PAH rats. And we further discover the mRNA of eIF2α has a common sequence with N 6-methyladenosine (m⁶A) modification by bioinformatics analysis, and the expression of METTL3, WTAP, and YTHDF1 is upregulated in MCT-PAH rats. These findings suggest a potentially novel mechanism by which eIF2α is upregulated by m⁶A modification in MCT-PAH rats, which is involved in the pathogenesis of PAH.

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m6A修饰上调eIF2α可促进mct诱导的肺动脉高压大鼠肺动脉平滑肌细胞增殖。

肺动脉高压(PAH)是一种恶性心血管疾病。真核起始因子2α (eIF2α)在低氧肺动脉高压(HPH)大鼠肺动脉平滑肌细胞(PASMCs)增殖中起重要作用。然而，eIF2α在PAH大鼠中的调节机制尚不清楚。本研究发现，eIF2α在MCT诱导的PAH大鼠中显著上调，eIF2α可通过mRNA甲基化上调，上调后的eIF2α可促进MCT-PAH大鼠的PASMC增殖。eIF2α抑制剂GSK2606414可下调eIF2α在MCT-PAH大鼠中的表达，减轻PASMC的增殖。通过生物信息学分析，我们进一步发现eIF2α mRNA与n6 -甲基腺苷(m6A)修饰有共同序列，并且METTL3、WTAP和YTHDF1在MCT-PAH大鼠中表达上调。这些发现提示了MCT-PAH大鼠中m6A修饰上调eIF2α的潜在新机制，该机制参与了PAH的发病机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cardiovascular Translational Research CARDIAC & CARDIOVASCULAR SYSTEMS-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

6.10

自引率

2.90%

发文量

148

审稿时长

6-12 weeks

期刊介绍： Journal of Cardiovascular Translational Research (JCTR) is a premier journal in cardiovascular translational research. JCTR is the journal of choice for authors seeking the broadest audience for emerging technologies, therapies and diagnostics, pre-clinical research, and first-in-man clinical trials. JCTR''s intent is to provide a forum for critical evaluation of the novel cardiovascular science, to showcase important and clinically relevant aspects of the new research, as well as to discuss the impediments that may need to be overcome during the translation to patient care.