The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells

Jingyan Han, Robert M. Weisbrod, Di Shao, Yosuke Watanabe, Xiaoyan Yin, Markus M. Bachschmid, Francesca Seta, Yvonne M.W. Janssen-Heininger, Reiko Matsui, Mengwei Zang, Naomi M. Hamburg, Richard A. Cohen

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)306-319
Number of pages14
JournalRedox Biology
Volume9
DOIs
StatePublished - Oct 1 2016

Keywords

  • Actin cytoskeleton
  • ApoE-deficient mice
  • Endothelial barrier function
  • Glutaredoxin-1
  • Protein S-glutathionylation
  • Small Rho GTPase Rac1

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells'. Together they form a unique fingerprint.

Cite this