Zhang Jing, Huang Wen-Qian, Zhang Yu-Rong, Liang Na, Li Nan-Ping, Tan Gang-Kai, Gong Shao-Xin, Wang Ai-Ping
Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, People's Republic of China.
J Cardiovasc Transl Res. 2024 Jun;17(3):598-608. doi: 10.1007/s12265-023-10458-7. Epub 2023 Nov 16.
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 (mA) 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 mA modification in MCT-PAH rats, which is involved in the pathogenesis of PAH.
肺动脉高压（PAH）是一种恶性心血管疾病。真核起始因子2α（eIF2α）在低氧诱导的肺动脉高压（HPH）大鼠的肺动脉平滑肌细胞（PASMCs）增殖中起重要作用。然而，在PAH大鼠中，eIF2α的调节机制仍知之甚少。在此，我们发现eIF2α在野百合碱（MCT）诱导的PAH大鼠中显著上调，eIF2α可通过mRNA甲基化上调，且上调的eIF2α可促进MCT-PAH大鼠的PASMC增殖。eIF2α抑制剂GSK2606414可下调MCT-PAH大鼠中eIF2α的表达并减轻PASMC增殖。并且我们通过生物信息学分析进一步发现eIF2α的mRNA具有与N6-甲基腺苷（mA）修饰的共同序列，且MCT-PAH大鼠中METTL3、WTAP和YTHDF1的表达上调。这些发现提示了一种潜在的新机制，即MCT-PAH大鼠中eIF2α通过mA修饰上调，这参与了PAH的发病机制。
