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

Purpose: Eukaryotic initiation factor 2 alpha (eIF2 alpha) 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 eIF2 alpha and autophagy in the vascular remodeling of the monocrotaline-induced PAH rats and to clarify the correlation between eIF2 alpha 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 eIF2 alpha, 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, eIF2 alpha was increased in the PDGF-induced PASMCs proliferation, and the expression of p62 was reduced in the PDGF-induced PASMCs proliferation. Moreover, eIF2 alpha siRNA downregulated the expression of eIF2 alpha and LC3B, and upregulated the expression of p62 in PDGF-induced PASMCs proliferation. eIF2 alpha 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 eIF2 alpha promotes the proliferation of PASMCs and vascular remodeling in monocrotaline-induced PAH rats through accelerating autophagy pathway.