Fos-related antigen-1 (Fra-1) is a member of the activator protein-1 transcription factor superfamily. It plays important roles in oncogenesis in various types of malignancies. Herein, we investigated the expression of Fra-1 in lung cancer tissues by qPCR, immunohistochemistry, and western blot technologies. The results showed that Fra-1 was overexpressed in the lung cancer tissues when compared with the level in the adjacent non-cancerous tissues. To explore the possible mechanism of Fra-1 in lung cancer, we elucidated the effect of Fra-1 on the apoptosis of lung cancer H460 cells, and found that the rate of cell apoptosis was decreased in the H460/Fra-1 cells compared with the H460 or H460/vector cells. Cell apoptosis is closely related with a reduction in mitochondrial membrane potential (ΔΨm) and an increase in intracellular reactive oxygen species (ROS) and calcium ion (Ca2+) concentrations. Our results showed that overexpression of Fra-1 in the lung cancer H460 cells, led to an increase in ΔΨm and and a decrease in intracellular ROS and Ca2+ concentrations. Furthermore, we found that Fra-1 was correlated with dysregulation of the P53 signaling pathway in lung cancer tissues in vitro. At the same time, we found that Fra-1 overexpression affected the expression of MDM2 and P53 in vivo. In summary, our results suggest that Fra-1 is upregulated in lung cancer tissues and functions by affecting the P53 signaling pathway in lung cancer.

The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS-IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS-IV on hypoxia-induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O 2); iii) treatment, hypoxia + intragastrical administration of AS-IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS-IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS-IV treatment on the development of hypoxia-induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS-IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS-IV treatment, 5 mmol/l γ-secretase inhibitor [N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch-3, Jagged-1, hes family bHLH transcription factor 5 (Hes-5) and PCNA were measured via reverse transcription-quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia-induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS-IV treatment alleviated PAH and prevented RV hypertrophy. AS-IV also inhibited hypoxia-induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS-IV treatment inhibited hypoxia-induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia-treated PAH model rats and cultured PASMCs, AS-IV treatment reduced the expression levels of Jagged-1, Notch-3 and Hes-5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS-IV in vitro and in vivo. Collectively, the results indicated that AS-IV effectively reversed hypoxia-induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS-IV for treatment of vascular diseases, such as PAH.

Chinese herbal medicine for CGSHY may lower the blood pressure smoothly and recover the circadian rhythm of blood pressure in EH patients. They may also improve the carotid elasticity of EH patients similar to that of Enalapril. The mechanism of action of Chinese herbs on EH might be related to the regulation of vascular endothelium function.

During hypoxia-induced pulmonary hypertension (HPH), pulmonary artery smooth muscle cells (PASMCs) proliferate as part of the characteristic pulmonary vascular remodeling. We investigated the expression of mitofusin 2(Mfn2) and its role in maintaining the balance between PASMC proliferation and apoptosis during hypoxia. In an experimental model of HPH, we exposed rats to hypoxia (10% ± 0.5% O2) or room air for 4 weeks. We found that Mfn2 messenger RNA and protein levels were reduced and that proliferating cell nuclear antigen protein expression was upregulated in HPH rat lung tissues. We also exposed primary cultured PASMCs from rat pulmonary arterioles to normoxia (21% O2/5% CO2) or hypoxia (2.5% O2/5% CO2) for 24 hours. We found that PASMC proliferation increased under hypoxic conditions and that more hypoxic cells than normoxic cells entered the S + G2/M phase. Additionally, phosphorylated Akt and proliferating cell nuclear antigen expression increased, whereas Mfn2 expression, cleaved caspase 9 expression, and the ratio of mitochondrial to cytosolic cytochrome C expression each decreased. These hypoxia-induced effects were reversed in PASMCs by Mfn2 overexpression and by phosphatidylinositide 3-kinases (PI3K) inhibition. Our results indicate that downregulation of Mfn2 in HPH may activate the PI3K/Akt pathway, thereby causing more cells to enter the S + G2/M phase of the cell cycle and inhibiting the mitochondrial apoptosis pathway.