The correlation of IRE1α oxidation with Nox4 activation in aging-associated vascular dysfunction

Abstract

Oxidative stress attributable to the activation of a Nox4-containing NADPH oxidase is involved in aging-associated vascular dysfunction. However, the Nox4-induced signaling mechanism for the vascular alteration in aging remains unclear. In an aged aorta, the expression of Nox4 mRNA and protein by Nox family of genes was markedly increased compared with a young aorta. Nox4 localization mainly to ER was also established. In the aorta of Nox4 WT mice aged 23–24 months (aged), reactive oxygen species (ROS) and endoplasmic reticulum (ER)/oxidative stress were markedly increased compared with the counter KO mice. Furthermore, endothelial functions including eNOS coupling process and acetylcholine-induced vasodilation were significantly disturbed in the aged WT, slightly affected in the counter KO aorta. Consistently, in d -galactose-induced in vitro aging condition, ER-ROS and its associated ER Nox4 expression and activity were highly increased. Also, in chronic d -galactose-treated condition, IRE1α phosphorylation and XBP-1 splicing and were transiently increased, but IRE1α sulfonation was robustly increased in the aging Nox4 WT condition when compared to the counter KO condition. In vitro D-gal-induced aging study, the phenomenon were abrogated with Nox4 knock-down condition and was significantly decreased in GKT, Nox4 inhibitor and 4-PBA, ER chemical chaperone-treated human umbilical vein endothelial cells. The state of Nox4-based ER redox imbalance/ROS accumulation is suggested to determine the pathway “the UPR; IRE1α phosphorylation and XBP-1 splicing and the UPR failure; IRE1α cysteine-based oxidation, especially sulfonation, finally controlling aging-associated vascular dysfunction.

Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma

“…Gefitinib had increased NADPH Oxidase-2 (NOX2) and NOX4 protein expression in H4 cells ( Figure 4 H). These NOX family members are likely involved in IRE1-mediated ER stress [ 26 ]. Our findings suggest substantial roles played by free Ca 2+ and ROS in the gefitinib-induced ER stress and apoptosis, with NOX2/4 as candidate sources for ROS generation.…”

“…ER-associated NOXs is one means of turning on the IRE1/JNK/Noxa axis through ROS generation [ 26 , 27 ]. Gefitinib increased NOX2/4 protein expression and ROS generation in glioma cells.…”

NADPH Oxidase 5 Induces Changes in the Unfolded Protein Response in Human Aortic Endothelial Cells and in Endothelial-Specific Knock-in Mice

“…Firstly, PDI promotes NOX activation by regulating subunit assembling [ 35 , 36 ]. Secondly, NOX2 and NOX4 are involved in UPR regulation [ 11 , 22 ]. In this way, calnexin stablishes molecular complexes with NOX4, necessary for the appropriate function of this enzyme [ 37 ].…”

“…NOX4 was shown to interact physically with UPR components as protein disulfide isomerase (PDI) and, otherwise, UPR activation can induce NOX4 expression and ROS production [ 21 ]. Additionally, NOX4 specifically oxidizes the ER stress sensor of the endoplasmic reticulum to nucleus signaling 1 alpha (IRE1α), which triggers phosphorylation and activation of the X-box binding protein 1 (XBP1), leading to proteasome activation or apoptosis induction [ 22 ]. Additionally, NOX2 and NOX4 increase their activity under ER stress conditions [ 23 ].…”

Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

“…The increased NAD(P)H oxidase activity results in the oxidation of BH 4 , a cofactor of eNOS, and the production of reactive oxygen species (ROS) [ 97 ]. ROS production by NAD(P)H oxidase may amplify ER stress [ 98 ]. The association between eNOS and ER stress may be due to chronic hyperglycemia, which increases oxidative stress [ 99 ].…”