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. 2015 Nov-Dec;29(8):984-92.
doi: 10.1016/j.jdiacomp.2015.07.016. Epub 2015 Jul 18.

Glycated human serum albumin induces NF-κB activation and endothelial nitric oxide synthase uncoupling in human umbilical vein endothelial cells

Bruno K Rodiño-Janeiro  1 , Beatriz Paradela-Dobarro  1 , Sergio Raposeiras-Roubín  1 , Mercedes González-Peteiro  2 , José R González-Juanatey  1 , Ezequiel Álvarez  3
Affiliations

Glycated human serum albumin induces NF-κB activation and endothelial nitric oxide synthase uncoupling in human umbilical vein endothelial cells

Bruno K Rodiño-Janeiro et al. J Diabetes Complications. 2015 Nov-Dec.

Abstract

Aims: Non-enzymatic glycated proteins could mediate diabetes vascular complications, but the molecular mechanisms are unknown. Our objective was to find new targets involved in the glycated human serum albumin (gHSA)-enhanced extracellular reactive oxygen species (ROS) production in human endothelial cells.

Methods & results: Some nuclear factors and phosphorylation cascades were analysed. gHSA activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which up-regulated NOX4 and P22PHOX and enhanced ROS production. Pharmacological inhibition of NF-κB reversed gHSA-enhanced NOX4 expression and decreased gHSA-induced ROS production in extra- and intracellular spaces. The inhibition of activator protein-1 (AP-1) induced a rise in NOX4 and P22PHOX subunit expression and a down-regulation of endothelial nitric oxide synthase (eNOS). AP-1 inhibition also enhanced extracellular ROS production in the presence of serum albumin, but not with gHSA. These results were explained by the eNOS uncoupling induced by gHSA, also demonstrated in this study. Phosphatidylinositol 3-kinase or mitogen-activated protein kinase kinase 1/2 did not show to be involved in gHSA-induced ROS production.

Conclusions: All together, the results suggested that gHSA-enhanced ROS production in endothelium is mediated by: 1) NF-κB activation and subsequence up-regulation of NADPH oxidase, 2) eNOS uncoupling. AP-1, although is not directly affected by gHSA, is another target for regulating NADPH oxidase and eNOS expression in endothelial cells.

Keywords: Amadori adducts; Endothelial dysfunction; Glycated albumin; NF-κB; Reactive oxygen species.

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