FUT8-Mediated Core Fucosylation Promotes the Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

by Selleckchem | Jul 08 2023

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease with unclear underlying molecular mechanisms and limited therapeutic options. This study aimed to explore the role of core fucosylation and the only glycosyltransferase FUT8 in PAH. We observed increased core fucosylation in a monocrotaline (MCT)-induced PAH rat model and isolated rat pulmonary artery smooth muscle cells (PASMCs) treated with platelet-derived growth factor-BB (PDGF-BB). We found that 2-fluorofucose (2FF), a drug used to inhibit core fucosylation, improved hemodynamics and pulmonary vascular remodeling in MCT-induced PAH rats. In vitro, 2FF effectively restrains the proliferation, migration, and phenotypic switching of PASMCs and promotes apoptosis. Compared with controls, serum FUT8 concentration in PAH patients and MCT-induced rats was significantly elevated. FUT8 expression appeared increased in the lung tissues of PAH rats, and the colocalization of FUT8 with α-SMA was also observed. SiRNA was used to knockdown FUT8 in PASMCs (siFUT8). After effectively silencing FUT8 expression, phenotypic changes induced in PASMCs by PDGF-BB stimulation were alleviated. FUT8 activated the AKT pathway, while the admission of AKT activator SC79 could partially counteract the negative effect of siFUT8 on the proliferation, apoptotic resistance, and phenotypic switching of PASMCs, which may be involved in the core fucosylation of vascular endothelial growth factor receptor (VEGFR). Our research confirmed the critical role of FUT8 and its mediated core fucosylation in pulmonary vascular remodeling in PAH, providing a potential novel therapeutic target for PAH.

Comments:

The study you described aimed to investigate the involvement of core fucosylation and the glycosyltransferase FUT8 in the development of pulmonary arterial hypertension (PAH). PAH is a progressive cardiopulmonary disease characterized by increased blood pressure in the pulmonary arteries and limited treatment options.

The researchers first examined core fucosylation levels in a rat model of PAH induced by monocrotaline (MCT) and in isolated rat pulmonary artery smooth muscle cells (PASMCs) treated with platelet-derived growth factor-BB (PDGF-BB). They observed increased core fucosylation in both the PAH rat model and the treated PASMCs.

To further investigate the potential therapeutic role of inhibiting core fucosylation, the researchers used a drug called 2-fluorofucose (2FF) known to inhibit this process. They found that administration of 2FF improved hemodynamics (blood flow) and pulmonary vascular remodeling in the MCT-induced PAH rat model. In vitro experiments demonstrated that 2FF effectively suppressed the proliferation, migration, and phenotypic switching of PASMCs and promoted apoptosis (programmed cell death).

Next, the researchers examined the concentration of FUT8, the only glycosyltransferase involved in core fucosylation, in serum samples from PAH patients and MCT-induced rats. They found that both PAH patients and MCT-induced rats exhibited significantly elevated levels of FUT8 compared to controls. The researchers also observed increased FUT8 expression in the lung tissues of PAH rats, along with colocalization of FUT8 with α-SMA, a marker for smooth muscle cells.

To investigate the functional role of FUT8 in PASMCs, the researchers used small interfering RNA (siRNA) to knock down FUT8 expression (siFUT8). Silencing FUT8 expression alleviated the phenotypic changes induced in PASMCs by PDGF-BB stimulation. This suggested that FUT8 plays a role in the abnormal behavior of PASMCs in PAH.

Furthermore, the researchers found that FUT8 activated the AKT pathway, a signaling pathway involved in cell survival and proliferation. When an AKT activator called SC79 was administered alongside siFUT8, it partially counteracted the negative effects of siFUT8 on the proliferation, apoptotic resistance, and phenotypic switching of PASMCs. This suggests that the AKT pathway may be involved in the core fucosylation of vascular endothelial growth factor receptor (VEGFR), a receptor involved in cell signaling.

Overall, this research provides evidence for the critical role of FUT8 and its mediated core fucosylation in pulmonary vascular remodeling in PAH. It suggests that targeting FUT8 and core fucosylation could serve as a potential therapeutic strategy for PAH. However, further studies are needed to validate these findings and explore the translational potential of this novel therapeutic target.