Down-regulation of lncRNA Gas5 promotes hypoxia-induced pulmonary arterial smooth muscle cell proliferation by regulating KCNK3 expression

Pulmonary hypertension (PH) is a progressive and potentially serious lung disease, defined by an abnormal elevation of pulmonary arterial pressure. PH occurs for many reasons, and hypoxia is considered as an important stimulus for the disease. Proliferation and migration of pulmonary artery smooth muscular cells (PASMCs) in the small peripheral pulmonary arteries are common characteristic features in hypoxia-induced PH (HPH). However, the mechanisms involved in the hypoxia-induced cell proliferation and migration are not clear. The aim of the present study was to investigate the role of lncRNA Gas5 in the hypoxia-stimulated proliferation and migration of human PASMCs (hPASMCs). We found that the expression of Gas5 was down-regulated in a rat model with hypoxia and in cultured hypoxic hPASMCs, and silence of Gas5 significantly promoted hPASMCs proliferation and migration in both normal and hypoxia condition. Subsequent studies revealed that miR-23b-3p interacted with Gas5 by directly targeting the miRNA-binding site in the Gas5 sequence, and qRT-PCR results showed miR23b-3p and Gas5 could affect each other's expression, respectively. Further study demonstrated that Gas5 acted as a competing endogenous RNA (ceRNA) for miR-23b-3p to modulate the KCNK3 expression, and these interactions led to promotion of hPASMCs proliferation and migration. This study identified that Gas5/miR-23b3p/KCNK3 axis may be a mechanism that hypoxia-induced PASMCs proliferation and migration, providing a strategy for clinical treatment of HPH in the future.