S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating the activity of nuclear factor κB (NF-κB) and actin polymerization. Vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) migration is inhibited by Glrx overexpression. In mice overexpressing Glrx, blood flow recovery, exercise function and capillary density were significantly attenuated after hindlimb ischaemia (HLI). Wnt5a and soluble Fms-like tyrosine kinase-1 (sFlt-1) were enhanced in the ischaemic-limb muscle and plasma respectively from Glrx transgenic (TG) mice. A Wnt5a/sFlt-1 pathway had been described in myeloid cells controlling retinal blood vessel development. Interestingly, a Wnt5a/sFlt-1 pathway was found also to play a role in EC to inhibit network formation. S-glutathionylation of NF-κB components inhibits its activation. Up-regulated Glrx stimulated the Wnt5a/sFlt-1 pathway through enhancing NF-κB signalling. These studies show a novel role for Glrx in post-ischaemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in pathological conditions including diabetes.
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Conference Article|
November 17 2014
Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway
Colin E. Murdoch;
Colin E. Murdoch
1
*Vascular Medicine Section, Aston Medical School Aston University, Aston Triangle, Birmingham B47 ET, U.K.
1To whom correspondence should be addressed (emailc.murdoch@aston.ac.uk).
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Markus M. Bachschmid;
Markus M. Bachschmid
†Vascular Biology Section, Boston University Medical School, Boston, MA 02118, U.S.A.
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Reiko Matsui
Reiko Matsui
†Vascular Biology Section, Boston University Medical School, Boston, MA 02118, U.S.A.
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Publisher: Portland Press Ltd
Received:
August 04 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (6): 1665–1670.
Article history
Received:
August 04 2014
Citation
Colin E. Murdoch, Markus M. Bachschmid, Reiko Matsui; Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway. Biochem Soc Trans 1 December 2014; 42 (6): 1665–1670. doi: https://doi.org/10.1042/BST20140213
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