Drug Design, Development and Therapy (2019-08-01)

eIF2α promotes vascular remodeling via autophagy in monocrotaline-induced pulmonary arterial hypertension rats

  • Guo L,
  • Li Y,
  • Tian Y,
  • Gong S,
  • Chen X,
  • Peng T,
  • Wang A,
  • Jiang Z

Journal volume & issue
Vol. Volume 13
pp. 2799 – 2809

Abstract

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Linya Guo,1,* Yanbing Li,2,3,* Ying Tian,4,5,* Shaoxin Gong,6 Xi Chen,1 Tianhong Peng,1 Aiping Wang,1,4,5,7 Zhisheng Jiang71Clinical Anatomy & Reproductive Medicine Application Institute, School of Medicine, University of South China, Hengyang 421001, People’s Republic of China; 2National Key Discipline of Human Anatomy, Southern Medical University, Guangzhou 510000, Guangdong, People’s Republic of China; 3Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangzhou, 510000, Guangdong, People’s Republic of China; 4Institute of Clinical Research, Affiliated Nanhua Hospital, University of South China, Hengyang 421002, Hunan, People’s Republic of China; 5Postdoctoral Research Institute on Basic Medicine, University of South China, Hengyang, 421001, Hunan, People’s Republic of China; 6Department of Pathology, First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, People’s Republic of China; 7Key Laboratory for Arteriosclerology of Hunan Province, Institute of Cardiovascular Disease, University of South China, Hengyang 421001, Hunan, People’s Republic of China*These authors contributed equally to this workPurpose: Eukaryotic initiation factor 2α (eIF2α) plays important roles in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in animal hypoxia-induced pulmonary hypertension models. However, the underlying mechanism remains unknown at large. Autophagy has been reported to play a key role in the vascular remodeling in pulmonary arterial hypertension (PAH). The purposes of this study are to determine the functions of eIF2α and autophagy in the vascular remodeling of the monocrotaline-induced PAH rats and to clarify the correlation between eIF2α and autophagy.Methods: We established a rat model of monocrotaline-induced PAH, and we established a cell model of platelet derived growth factor (PDGF)-induced PASMCs proliferation. The vascular morphology and the expression of eIF2α, LC3B, and p62 were assessed in the pulmonary arterial tissue of Sprague-Dawleyrats and PDGF-induced PASMCs.Results: Autophagy was significantly active in monocrotaline model group (MCT)-induced PAH rats, which obviously promotes vascular remodeling in MCT-induced PAH rats. Furthermore, the proliferation of PASMCs was induced by PDGF in vitro. The expression of LC3B, eIF2α was increased in the PDGF-induced PASMCs proliferation, and the expression of p62 was reduced in the PDGF-induced PASMCs proliferation. Moreover, eIF2α siRNA downregulated the expression of eIF2α and LC3B, and upregulated the expression of p62 in PDGF-induced PASMCs proliferation. eIF2α siRNA inhibited the PDGF-induced PASMCs proliferation. Finally, chloroquine can upregulate the protein expression of LC3B and p62, it also can inhibit proliferation in PDGF-induced PASMCs.Conclusion: Based on these observations, we conclude that eIF2α promotes the proliferation of PASMCs and vascular remodeling in monocrotaline-induced PAH rats through accelerating autophagy pathway.Keywords: eIF2α, autophagy, PASMCs, PAH, monocrotaline

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