Stox1 induced the proliferation and cell cycle arrest in pulmonary artery smooth muscle cells via AKT signaling pathway.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the vascular remodeling that also involves proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Overexpression of Storkhead box (STOX1) regulates genes involved hypoxia, redox balance, nitric oxide, and energy metabolism. In this study, we supposed Stox1 adjusted cells proliferation and migration in PASMCs development and played an important role in the pulmonary arterial vascular remodeling. Hemodynamic assay and Right ventricular morphometric assay were used to check the rat model of PAH. HE staining was used to examine the arterial wall thickness. Masson staining showed that the deposition of collagen was significantly increased in PAH. In addition, Stox1 were assessed by immunofluorescence and immunohistochemistry staining. The effect of Stox1 on PASMCs was assessed by cell counting Kit-8 assay (CCK-8 assay), Scratch-Wound assay, EdU staining assay, Cell cycle analysis and Western blot. Right ventricular systolic pressure (RVSP) and right ventricular were significantly increased in hypoxia group and monocrotaline group compared to control group. The expression of Stox1 was increased in lung tissues in PAH rats. In vitro, the expression of Stox1 was up-regulated with time-dependent manner in hypoxia condition. Meanwhile, Stxo1 promoted the proliferation and migration in hypoxia-treated PASMCs. Moreover, we found that hypoxia promoted the expression of PCNA, Cyclin E and Cyclin A, increased more cells from G0/G1 phase to S phase and induced the activation of AKT proteins, which was significantly attenuated by inhibition of Stox1 expression in PASMCs. These findings indicated that Stox1 induced proliferation of PASMCs and the effect is, at least in part, mediated through AKT signaling pathway.

Xu Y ，Sun Z ，Wang Q ，Wang T ，Liu Y ，Yu F ... -  《-》

LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension.

Lei S ，Peng F ，Li ML ，Duan WB ，Peng CQ ，Wu SJ ... -  《-》

Protective effects of dioscin on vascular remodeling in pulmonary arterial hypertension via adjusting GRB2/ERK/PI3K-AKT signal.

Pulmonary arterial hypertension (PAH) is a progressive and lethal cardiopulmonary. Pulmonary vascular remodeling (PVR) caused by excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) is the chief pathological feature of PAH. Dioscin is a natural product that possesses multiple pharmacological activities, but its effect on PAH remains unclear. In this study, effect of dioscin on vascular remodeling in PAH was assessed in hypoxia-induced PASMCs, hypoxia-induced and monocrotaline (MCT)-induced rats. Western blot, Real-time PCR and siRNA transfection tests were applied to evaluate the possible mechanisms of dioscin. In vitro experiments, results showed dioscin markedly inhibited the proliferation and migration, and promoted apoptosis of hypoxic PASMCs. In vivo, dioscin significantly decreased the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI), and improved pulmonary vascular stenosis in rats induced by hypoxia or MCT. Molecular mechanism studies showed that dioscin significantly reduced the expression of growth factor receptor-bound protein 2 (GRB2). Subsequently, dioscin reduced the expressions of Ras, Cyclin D1, CDK4, c-Fos, PCNA and p-ERK to inhibit proliferation and migration of PASMCs, inhibited p-PI3K and p-AKT levels and increased Bax/Bcl2 ratio to promote cell apoptosis. GRB2 siRNA transfection in PASMCs further confirmed that the inhibitory action of dioscin in PAH was evoked by adjusting GRB2/ERK/PI3K-AKT signal. Taken together, our study indicated that dioscin attenuates PAH through adjusting GRB2/ERK/PI3K-AKT signal to inhibit PASMCs proliferation and migration, and promote apoptosis, and dioscin may be developed as a therapeutic strategy for treating PAH in the future.

Yang Y ，Yin L ，Zhu M ，Song S ，Sun C ，Han X ，Xu Y ，Zhao Y ，Qi Y ，Xu L ，Peng JY ... -  《-》

miR-143 and miR-145 promote hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells through regulating ABCA1 expression.

Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) play an important role in the occurrence and development of pulmonary arterial hypertension (PAH). miR-143/145 was reported to be up-regulated in the animal models and PAH patients, and deletion of miR-143/145 cluster prevented the development of hypoxia-induced pulmonary hypertension, but its underlying mechanism has not been elucidated. qRT-PCR and Western blot were performed to detect the expressions of miR-143/145 and ATP-binding cassette transporter A1 (ABCA1) in PAH patients and PASMCs under hypoxic conditions. Cell proliferation and migration were assessed by Cell Counting Kit-8 and wound-healing assay, respectively. Luciferase reporter assay and RNA immunoprecipitation were conducted to confirm the interaction between miR-143/145 and ABCA1. Hypoxia-induced PAH rat model was established to confirm the functions of miR-143/145 in the pathogenesis of PAH and its underlying mechanism in vivo. miR-143 and miR-145 were up-regulated and ABCA1 was down-regulated in PAH patients and PASMCs under hypoxic conditions for different time, as well as hypoxia-induced PAH rats. miR-143/145 inhibition and ABCA1 overexpression suppressed hypoxia-induced proliferation and migration in PASMCs. ABCA1 was identified as a direct target of miR-143/145 in PASMCs. Moreover, ABCA1 partially reversed miR-143/145-mediated promotion of hypoxia-induced cell proliferation and migration in PASMCs. Furthermore, in vivo experiments confirmed that inhibition of miR-143/145 prevents hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling by targeting ABCA1. miR-143/145 promoted hypoxia-induced proliferation and migration of PASMCs by targeting ABCA1, contributing to better understanding of the mechanism underlying the pathogenesis of PAH.

Yue Y ，Zhang Z ，Zhang L ，Chen S ，Guo Y ，Hong Y ... -  《-》

Histone demethylase JARID1B regulates proliferation and migration of pulmonary arterial smooth muscle cells in mice with chronic hypoxia-induced pulmonary hypertension via nuclear factor-kappa B (NFkB).

Chronic hypoxia-induced pulmonary hypertension (PH) is a disorder that is characterized by increased pulmonary arterial pressure resulting from lung diseases or shortage of oxygen in the body. Excess proliferation of pulmonary vascular cells such as pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of PH. Recent evidence indicates that, in addition to genetic predisposition and environmental factors, epigenetic mechanisms play a pivotal role in etiology of PH. In this study, we investigated the possible role played by jumonji AT-rich interactive domain 1B (JARID1B), a histone demethylase, in regulating the proliferation of vascular smooth muscle cells in chronic hypoxia-induced PH condition. Quantitative polymerase chain reaction analysis of samples from rats with PH showed an elevated expression of JARID1B in their PASMCs, positively correlating with increased nuclear factor-kappa B (NFkB) expression. Further functional studies in vitro indicated that overexpression of JARID1B increased the proliferation and migration of PASMCs, which were inhibited by depletion of NFkB. Genomewide transcriptional analysis revealed that the JARID1B regulated NFkB signaling pathway by directly binding to its promoter. We have also shown that JARID1B indirectly regulates the expression of vascular endothelial growth factor via NFkB signaling and hence may also play a crucial role in controlling PAECs, leading to changes in vascular architecture in PH. Our findings could lead to further studies on the role of JARID1B in PH etiology and therefore could lead to a potential therapeutic target for chronic hypoxia induced pulmonary hypertension.

Li Y ，Liu S ，Zhang Y ，Gao Q ，Sun W ，Fu L ，Cao J ... -  《-》