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Nox4 regulates the eNOS uncoupling process in aging endothelial cells

Title
Nox4 regulates the eNOS uncoupling process in aging endothelial cells
Author(s)
Lee, Hwa-YoungZeeshan, Hafiz Maher AliKim, Hyung-RyongChae, Han-Jung
DGIST Authors
Kim, Hyung-Ryong
Issued Date
2017-12
Type
Article
Article Type
Article
Author Keywords
Nox4ER stresseNOSSuperoxide anion radicalNO
Keywords
NITRIC-OXIDE SYNTHASEENDOPLASMIC-RETICULUM STRESSNADPH OXIDASESHEAT-SHOCK-PROTEIN-90IDENTIFICATIONLOCALIZATIONMITOCHONDRIADYSFUNCTIONSENESCENCEEXPRESSION
ISSN
0891-5849
Abstract
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. © 2017 Elsevier Inc.
URI
http://hdl.handle.net/20.500.11750/4852
DOI
10.1016/j.freeradbiomed.2017.09.010
Publisher
Elsevier Inc.
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