Nox4 regulates the eNOS uncoupling process in aging endothelial cells

Publication date: December 2017
Source:Free Radical Biology and Medicine, Volume 113
Author(s): Hwa-Young Lee, Hafiz Maher Ali Zeeshan, Hyung-Ryong Kim, Han-Jung Chae
ROS and its associated signaling contribute to vascular aging-associated endothelial disturbance. Since the non-effective endothelial nitric oxide synthase (eNOS) coupling status is related to vascular aging-related phenotypes, eNOS coupled/uncoupled system signaling was studied in human umbilical vein endothelial cells (HUVEC). Nitric oxide (NO) and eNOS Ser1177 were significantly decreased, whereas O2^- (superoxide anion radical) increased with passage number. In aging cells, NADPH oxidase 4 (Nox4), one of the main superoxide generating enzymes, and its associated protein disulfide isomerase (PDI) chaperone were highly activated, and the resultant ER redox imbalance leads to disturbance of protein folding capability, namely endoplasmic reticulum (ER) stress, ultimately inducing dissociation between HSP90 and IRE-1α or PERK, decreasing HSP90 stability and dissociating the binding of eNOS from the HSP90 and leading to eNOS uncoupling. Through chemical and Nox4 siRNA approaches, Nox4 and its linked ER stress were shown to mainly contribute to eNOS uncoupling and its associated signaling, suggesting that Nox4 and its related ER stress signaling are key signals of the aging process in endothelial cells.

Graphical abstract

http://ift.tt/2yg6SyG