Abstract
BackgroundPulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). LncRNA cancer susceptibility candidate 2 (CASC2) has been revealed to be involved in PASMC injury in hypoxia-induced pulmonary hypertension. However, the exact molecular mechanisms whereby CASC2 regulates PASMC proliferation and migration are still incompletely understood.MethodsThe expression levels of CASC2, miR-222 and inhibitor of growth 5 (ING5) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) assay. Wound healing assay was used to analyze cell migration ability. The relationship between miR-222 and CASC2 or ING5 was confirmed using bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay.ResultsCASC2 was down-regulated in hypoxia-induced PASMCs in a dose- and time-dependent manner. Functional experiments showed that CASC2 overexpression could reverse hypoxia-induced proliferation and migration of PASMCs. Bioinformatics analysis indicated that CASC2 acted as a competing endogenous RNA of miR-222, thereby regulating the expression of ING5, the downstream target of miR-222, in PASMCs. In addition, rescue assay suggested that the inhibition mediated by CASC2 of hypoxia-induced PASMC proliferation and migration could be attenuated by miR-222 inhibition or ING5 overexpression.ConclusionCASC2 attenuated hypoxia-induced PASMC proliferation and migration by regulating the miR-222/ING5 axis to prevent vascular remodeling and the development of PAH, providing a novel insight and therapeutic strategy for hypoxia-induced PAH.
Highlights
Pulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs)
These findings verified that cancer susceptibility candidate 2 (CASC2) was down-regulated in hypoxia-induced PASMCs and aberrantly expressed CASC2 might be related to the pathogenesis of PAH
Downregulated CASC2 promotes proliferation and migration of hypoxia-induced PASMCs To explore the potential biological functions of CASC2 in proliferation and migration of hypoxia-induced PASMCs, PASMCs were transfected with CASC2 or si-CASC2 prior to exposure to the hypoxia condition (3% O2), and the transfection efficiency was determined using quantitative real-time polymerase chain reaction (qRT-PCR) with the results of decreased CASC2 expression in PASMCs transfected with si-CASC2 and increased CASC2 expression in PASMCs transfected with CASC2 (Fig. 2a, b)
Summary
Pulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). LncRNA cancer susceptibility candidate 2 (CASC2) has been revealed to be involved in PASMC injury in hypoxia-induced pulmonary hypertension. The exact molecular mechanisms whereby CASC2 regulates PASMC proliferation and migration are still incompletely understood. The pathobiology of PAH is complex; excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia can result in the narrowing or occlusion of pulmonary vessels, which are the main cellular mechanisms of pulmonary vascular remodeling and affect the initiation and progression of PAH [2, 3]. Gong et al revealed that CASC2 could suppress PASMC proliferation and the phenotypic switch in hypoxia-induced pulmonary hypertension (PH), suggesting the possible regulatory role of CASC2 in the pathogenesis of PAH [15]. The exact molecular mechanisms of CASC2 in the development of PAH remain unclear
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