Maresin 1 intervention reverses experimental pulmonary arterial hypertension in mice.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a pulmonary vasculature obstructive disease that leads to right heart failure and death. Maresin 1 is an endogenous lipid mediator known to promote inflammation resolution. However, the effect of Maresin 1 on PAH remains unclear. EXPERIMENTAL APPROACH: The serum Maresin 1 concentration was assessed using UPLC. A mouse model of PAH was established by combining the Sugen 5416 injection and hypoxia exposure. After treatment with Maresin 1, the right ventricular systolic pressure (RVSP) and right ventricular function were measured by haemodynamic measurement and echocardiography, respectively. Vascular remodelling was evaluated by histological staining. Confocal microscopy and western blot were used to test related protein expression. In vitro cell migration, proliferation and apoptosis assays were performed in primary rat pulmonary artery smooth muscle cells (PASMCs). Western blotting and siRNA transfection were used to clarify the mechanism of Maresin 1. KEY RESULTS: Endogenous serum Maresin 1 was decreased in PAH patients and mice. Maresin 1 treatment decreased RVSP and attenuated right ventricular dysfunction (RVD) in the murine PAH model. Maresin 1 reversed abnormal changes in pulmonary vascular remodelling, attenuating endothelial to mesenchymal transformation and enhancing apoptosis of α-SMA positive cells. Furthermore, Maresin 1 inhibited PASMC proliferation and promoted apoptosis by inhibiting STAT, AKT, ERK, and FoxO1 phosphorylation via LGR6. CONCLUSION AND IMPLICATIONS: Maresin 1 improved abnormal pulmonary vascular remodelling and right ventricular dysfunction in PAH mice, targeting aberrant PASMC proliferation. This suggests Maresin 1 may have a potent therapeutic effect in vascular disease.

FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

The proliferation, migration and apoptotic resistance of pulmonary artery smooth muscle cells (PASMCs) are central to the progression of pulmonary arterial hypertension (PAH). Our previous study identified that fibroblast growth factor 21 (FGF21) regulates signalling pathway molecules, such as peroxisome proliferator-activated receptor gamma (PPARγ), to play an important role in PAH treatment. However, the biological roles of miRNAs in these effects are not yet clear. In this study, using miRNA sequencing and real-time PCR, we found that FGF21 treatment inhibited miR-130 elevation in hypoxia-induced PAH in vitro and in vivo. Dual luciferase reporter gene assays showed that miR-130 directly negatively regulates PPARγ expression. Inhibition of miR-130 expression suppressed abnormal proliferation, migration and apoptotic resistance in hypoxic PASMCs, and this effect was corrected upon PPARγ knockdown. Both the ameliorative effect of FGF21 on pulmonary vascular remodelling and the inhibitory effect on proliferation, migration and apoptotic resistance in PASMCs were observed following exogenous administration of miR-130 agomir. In conclusion, this study revealed the protective effect and mechanism of FGF21 on PAH through regulation of the miR-130/PPARγ axis, providing new ideas for the development of potential drugs for PAH based on FGF21.

FGF21 attenuates hypoxia­induced dysfunction and inflammation in HPAECs via the microRNA­27b­mediated PPARγ pathway.

Pulmonary arterial hypertension (PAH), is a chronic and progressive disorder characterized by pulmonary vascular remodeling, including endothelial cell dysfunction and inflammation. MicroRNAs (miRNAs or miRs) play an important role in the development of PAH. In addition, fibroblast growth factor 21 (FGF21) has been found to have marked anti-dysfunction and anti­inflammatory properties. Therefore, the present study aimed to investigate the latent effects of FGF21 against PAH through the miR­27b/peroxisome proliferator­activated receptor γ (PPARγ) axis. Human pulmonary arterial endothelial cells (HPAECs) subjected to hypoxia were used as PAH models. The results revealed that PPARγ expression was downregulated and miR­27b expression was upregulated in the HPAECs exposed to hypoxia. Luciferase assay suggested that PPARγ was a target gene of miR­27b. Furthermore, miR­27b inhibited the expression of the PPARγ gene, thereby aggravating hypoxia­induced HPAEC dysfunction. Moreover, miR­27b activated the nuclear factor­κB signaling pathway and the expression of inflammatory factors [interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α] by targeting PPARγ. In addition, the expression of miR­27b decreased following treatment of the hypoxia­exposed HPAECs with FGF21. Furthermore, FGF21 alleviated hypoxia­induced HPAEC dysfunction and inflammation by inhibiting miR­27b expression and thereby promoting PPARγ expression. On the whole, the findings of the present study suggest that FGF21 may serve as a therapeutic target for managing PAH through the miR­27b­mediated PPARγ pathway.

Downregulation of CPA4 inhibits non small-cell lung cancer growth by suppressing the AKT/c-MYC pathway.

Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. A previous study indicated that CPA4 may participate in the modulation of peptide hormone activity and hormone-regulated tissue growth and differentiation. However, the role of CPA4 in lung tumorigenesis remains unclear. Our study revealed that CPA4 expression was higher in both lung cancer cells and tumor tissues. We performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, colony-formation assays, and Cellomics ArrayScan Infinity analysis to demonstrate that CPA4 knockdown inhibited non small-cell lung cancer (NSCLC) cell proliferation. Conversely, ectopic expression of CPA4 enhanced lung cancer cell proliferation. Consistent with these observations, we generated xenograft tumor models to confirm that CPA4 downregulation suppressed NSCLC cell growth. Mechanistically, we revealed that CPA4 downregulation may induce apoptosis and G1-S arrest by suppressing the protein kinase B/c-MYC pathway. These results suggest that CPA4 has an oncogenic effect on lung cancer growth. Taken together, we identified a novel gene in lung cancer that might provide a basis for new therapeutic targets.