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

J Cardiovasc Transl Res. 2024 Jun;17(3):598-608. doi: 10.1007/s12265-023-10458-7. Epub 2023 Nov 16.

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.

Keywords: PASMCs; Pulmonary arterial hypertension; WTAP; eIF2α; m6A methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Animals
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Disease Models, Animal*
  • Eukaryotic Initiation Factor-2* / genetics
  • Eukaryotic Initiation Factor-2* / metabolism
  • Male
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Monocrotaline* / toxicity
  • Muscle, Smooth, Vascular* / drug effects
  • Muscle, Smooth, Vascular* / metabolism
  • Muscle, Smooth, Vascular* / pathology
  • Myocytes, Smooth Muscle* / drug effects
  • Myocytes, Smooth Muscle* / metabolism
  • Myocytes, Smooth Muscle* / pathology
  • Pulmonary Arterial Hypertension* / chemically induced
  • Pulmonary Arterial Hypertension* / genetics
  • Pulmonary Arterial Hypertension* / metabolism
  • Pulmonary Arterial Hypertension* / pathology
  • Pulmonary Arterial Hypertension* / physiopathology
  • Pulmonary Artery* / drug effects
  • Pulmonary Artery* / metabolism
  • Pulmonary Artery* / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley*
  • Signal Transduction
  • Up-Regulation*

Substances

  • Eukaryotic Initiation Factor-2
  • Monocrotaline
  • Adenosine
  • RNA, Messenger
  • N-methyladenosine
  • Methyltransferases