The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells
| Autor: | Naomi M. Hamburg, Richard A. Cohen, Mengwei Zang, Markus Bachschmid, Di Shao, Xiaoyan Yin, Yvonne M. W. Janssen-Heininger, Reiko Matsui, Yosuke Watanabe, Jingyan Han, Francesca Seta, Robert M. Weisbrod |
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| Rok vydání: | 2016 |
| Předmět: |
Male
rac1 GTP-Binding Protein 0301 basic medicine Apolipoprotein E Clinical Biochemistry Gene Expression Vascular permeability medicine.disease_cause Biochemistry Mice lcsh:QH301-705.5 Aorta Mice Knockout lcsh:R5-920 Actin cytoskeleton Endothelial barrier function Glutathione Cell biology Endothelial stem cell lcsh:Medicine (General) Oxidation-Reduction Research Paper RAC1 Oxidative phosphorylation Biology Cell Line Capillary Permeability Adherens junction ApoE-deficient mice 03 medical and health sciences Apolipoproteins E Metabolic Diseases Small Rho GTPase Rac1 Stress Physiological medicine Animals Humans Glutaredoxin-1 Cysteine Glutaredoxins Organic Chemistry Endothelial Cells 030104 developmental biology lcsh:Biology (General) Mutation Endothelium Vascular Protein S-glutathionylation Protein Processing Post-Translational Oxidative stress |
| Zdroj: | Redox Biology, Vol 9, Iss C, Pp 306-319 (2016) Redox Biology |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2016.09.003 |
| Popis: | Background 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. Methods and results 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. Conclusions Glutathionylation and inactivation of Rac1 in endothelial cells represent a novel redox mechanism of vascular barrier dysfunction associated with metabolic disorders. Graphical abstract fx1 Highlights • 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. |
| Databáze: | OpenAIRE |
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