CFTR ameliorates high glucose-induced oxidative stress and inflammation by mediating the NF-κB and MAPK signaling pathways in endothelial cells

Abstract

Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive production of oxidative stress and pro-inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regulator (CFTR). However, little information is available about the role of CFTR in hyperglycemia‑induced endothelial cell oxidative stress and inflammation. In the present study, a high glucose‑treatment was applied in human umbilical vein endothelial cells with CFTR overexpression or inhibition, and the oxidative and inflammatory characteristics were measured. It was shown that CFTR protein and mRNA expression were reduced by glucose in a concentration‑dependent manner. Overexpression of CFRT via adenoviral infection significantly inhibited the production of reactive oxygen species and inflammatory biomediators induced by high glucose. Conversely, pharmacological inhibition of CFTR led to the opposite effects. Mechanistically, nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinase (MAPK) signaling were activated following high glucose treatment, which were inhibited by CFTR overexpression and enhanced by CFTR inhibition. The pro‑inflammatory effect of CFTR inhibition was abolished by pharmacological inhibition of the NF‑κB or MAPK pathways. Moreover, inhibition of MAPK abrogated CFTR inhibition‑induced NF‑κB nuclear translocation, whereas NF‑κB inhibitor produced no effects on MAPK activation. Additionally, antioxidant treatment inhibited the high glucose‑induced decrease in CFTR expression and the increase in inflammatory responses. Collectively, these findings revealed that CFTR attenuates high glucose‑induced endothelial cell oxidative stress and inflammation through inactivation of NF‑κB and MAPK signaling, indicating that elevation of CFRT expression may be a novel strategy in preventing endothelial dysfunction in diabetes.

Effect of tryptase on mouse brain microvascular endothelial cells via protease-activated receptor 2

“…In type 2 diabetic mice, stimulation of PAR-2 can upregulate TNF-α expression [35]. MAPK and NF-kappa B signalling pathway are associated with the inflammation progress in endothelial cells [36]. Therefore, we examined the expression of TLR4 and TNF-α and MAPK and NF-kappa B signalling pathway-associated protein when PAR-2 on mouse brain microvascular endothelial cell was stimulated by tryptase.…”

Upregulation of CFTR Protects against Palmitate-Induced Endothelial Dysfunction by Enhancing Autophagic Flux

“…Here, we further investigate if other ion channels participate in PA-induced endothelial dysfunction. CFTR is an ATP-gated Cl − channel, and downregulation of CFTR causes apoptosis via ROS and inflammation in renal cells, vascular smooth muscle cells, and other cell types [ 23 , 38 – 40 ]. In this study, we found that CFTR expression decreased in PA-insulted endothelial cells; Forskolin significantly inhibited PA-induced endothelial dysfunction showing as increasing cell viability, inhibiting cell apoptosis, reducing ROS generation, and restoring NO generation.…”

“…A large number of studies showed that CF patients had endothelial perturbation and microvascular dysfunction [ 15 – 20 ], suggesting that CFTR deficiency contributes to endothelial dysfunction. Besides, CFTR was showed to protect against endothelial apoptosis from oxidative stress and inflammation [ 21 – 23 ]. Recently, several researches demonstrated that CFTR regulated autophagy in the intestinal cancer cells, lipopolysaccharide-induced acute lung injury, and the immune response in CF [ 24 – 26 ].…”

Endothelial cells secreted ET-1 augments DN via inducing EM accumulation of MCs in ETBR−/− mice

“…RelA/p65, c-Rel and RelB, plays a critical role in inflammatory process and metabolic disease [18]. It has been reported that high blood glucose, urinary albumin, angiotensin II could contribute to NF-kappaB activation [19,20]. Evidence have shown that NF-kappaB activation in endothelial cells exerted a vital role in DN.…”