Abstract
Abnormal functional changes in pulmonary artery smooth muscle cells are the main causes of many lung diseases. Among, autophagy plays a crucial role. However, the specific molecular regulatory mechanism of autophagy in PASMCs remains unclear. Here, we first demonstrate that BCAT1 played a key role in the autophagy of hypoxic PASMCs and hypoxic model rats. BCAT1-induced activation and accumulation of the autophagy signaling proteins BECN1 and Atg5 by the endoplasmic reticulum (ER) stress pathway. Interestingly, we discovered that BCAT1 bound IRE1 on the ER to activate expression of its downstream pathway XBP-1-RIDD axis to activate autophagy. More importantly, we identified an RNA-binding protein, zinc finger protein 423, which promoted autophagy by binding adenylate/uridylate (AU)-rich elements in the BCAT1 mRNA 3′-untranslated region. Overall, our results identify BCAT1 as a potential therapeutic target for the clinical treatment of lung diseases and reveal a novel posttranscriptional regulatory mechanism and signaling pathway in hypoxia-induced PASMC autophagy.
Highlights
Smooth muscle cells in the vessel wall are the main cell type essential for the structural and functional integrity of blood vessels
Hypoxia upregulates the expression of BCAT1 First, to confirm the expression of BCAT1 in pulmonary artery smooth muscle cells (PASMCs), PASMCs were maintained under hypoxia for 24 h
Our results showed that interference with IRE1 could significantly reverse the increased expression of autophagy-related proteins induced by overexpression of BCAT1, which indicated that the combined effect of BCAT1 and IRE1 caused by hypoxia was related to the activation of PASMC autophagy (Fig. 4a and Fig. S5b)
Summary
Smooth muscle cells in the vessel wall are the main cell type essential for the structural and functional integrity of blood vessels. Abnormal functional changes in pulmonary artery smooth muscle cells (PASMCs) are the main cause of many lung diseases. Lung diseases, including pulmonary hypertension, pulmonary fibrosis, chronic obstructive pulmonary disease, and even lung cancer, are a type of disease with extremely high mortality[1,2,3]. The homeostasis of oxygen is an important factor in maintaining normal lung structure and function[7]. Increasing evidence shows that hypoxia has a significant effect on the behavior of many kinds of tumors, including non-small cell lung cancer (NSCLC)[8,9,10]. Hypoxia led to the upregulation of mitofusin 1, which maintains mitochondrial homeostasis through mir-125a, and was shown to play an important role in promoting PASMCs12. We reported that programmed death ligand 1 triggered pyroptosis and pulmonary fibrosis in hypoxic PASMCs9
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