The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells.
The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells.
复制标题
DOI：
10.1016/j.redox.2016.09.003
复制
发表时间：
2016-10
期刊：
影响因子：
11.4
通讯作者：
Cohen, Richard A.
中科院分区：
文献类型：
--
作者：
Han, Jingyan;Weisbrod, Robert M.;Shao, Di;Watanabe, Yosuke;Yin, Xiaoyan;Bachschmid, Markus M.;Seta, Francesca;Janssen-Heininger, Yvonne M. W.;Matsui, Reiko;Zang, Mengwei;Hamburg, Naomi M.;Cohen, Richard A.
关键词：
Oxidative stress is implicated in increased vascular permeability associated with metabolic disorders, but the underlying redox mechanism is poorly defined. S-glutathionylation, a stable adduct of glutathione with protein sulfhydryl, is a reversible oxidative modification of protein and is emerging as an important redox signaling paradigm in cardiovascular physiopathology. The present study determines the role of protein S-glutathionylation in metabolic stress-induced endothelial cell permeability. In endothelial cells isolated from patients with type-2 diabetes mellitus, protein S-glutathionylation level was increased. This change was also observed in aortic endothelium in ApoE deficient (ApoE-/-) mice fed on Western diet. Metabolic stress-induced protein S-glutathionylation in human aortic endothelial cells (HAEC) was positively correlated with elevated endothelial cell permeability, as reflected by disassembly of cell-cell adherens junctions and cortical actin structures. These impairments were reversed by adenoviral overexpression of a specific de-glutathionylation enzyme, glutaredoxin-1 in cultured HAECs. Consistently, transgenic overexpression of human Glrx-1 in ApoE-/- mice fed the Western diet attenuated endothelial protein S-glutathionylation, actin cytoskeletal disorganization, and vascular permeability in the aorta. Mechanistically, glutathionylation and inactivation of Rac1, a small RhoGPase, were associated with endothelial hyperpermeability caused by metabolic stress. Glutathionylation of Rac1 on cysteine 81 and 157 located adjacent to guanine nucleotide binding site was required for the metabolic stress to inhibit Rac1 activity and promote endothelial hyperpermeability. Glutathionylation and inactivation of Rac1 in endothelial cells represent a novel redox mechanism of vascular barrier dysfunction associated with metabolic disorders. In metabolically stressed endothelial cells, protein S-glutathionylation is elevated. glutaredoxin-1 diminishes protein S-glutathionylation and preserves aortic barrier function. Pharmacological inhibition of Rac1 abrogates Glrx1-mediated barrier protection. Glutathionylation of Rac1 is associated with a defect in Rac1 activation status.
登录
查看更多内容
影响因子：
5.5
作者：
Aslam, Muhammad;Schluter, Klaus-Dieter;Guenduez, Dursun
通讯作者：
Guenduez, Dursun
影响因子：
7.7
作者：
JeBailey, Lellean;Wanono, Oshrit;Klip, Amira
通讯作者：
Klip, Amira
影响因子：
20.1
作者：
Beckman, Joshua A.;Creager, Mark A.
通讯作者：
Creager, Mark A.
影响因子：
7.8
作者：
EDELHAUSER, HF;VANHORN, DL;PEDERSON, HJ
通讯作者：
PEDERSON, HJ
影响因子：
7.7
作者：
Guleria, Rakeshwar S.;Pan, Jing;Singh, Ugra S.
通讯作者：
Singh, Ugra S.