Background: Pulmonary hypertension (PH) is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Our lately study demonstrated that let-7g inhibited hypoxia-induced proliferation of PASMCs via repressing c-myc-Bmi1-p16 signaling pathway. However, the upstream of let-7g has not yet been fully defined. Previous studies have shown that LOX-1, a target of let-7g, could also regulate the expression of let-7g in human aortic endothelial cells. In this present study, we aimed to investigate whether there is a negative feedback regulation between microRNA let-7g and LOX-1 in hypoxia-induced proliferation of PASMCs. Methods: SD Rats were exposed to hypoxia (10% 02, 3 weeks) to induce PH. HE staining was used to evaluate pulmonary artery remodeling. in situ hybridization and immunohistochemistry were performed to assess the expression and distribution of let -7g and LOX-1, respectively. MTS, EDU and flow cytometry were performed to evaluate PASMCs proliferation. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted to assess the expression of let -7g, LOX-1, calpain-1,-2,-4, and OCT-1. Results: The expression of let -7g was significantly down -regulated in pulmonary arteries of hypoxiainduced PH rats accompanied by pulmonary vascular remodeling, whereas let -7g mimic inhibited hypoxia-induced proliferation of PASMCs and up-regulation of LOX-1 expression. LOX-1 blocking reversed hypoxia-induced down-regulation of let -7g expression. Calpains, protein kinase C and OCT-1 were involved in negative feedback regulation between let -7g and LOX-1. Conclusion: Negative feedback regulation between let -7g and LOX-1 mediated hypoxia-induced proliferation of in PASMCs. (C) 2017 Elsevier Inc. All rights reserved.