Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 12, Pages 8633-8644Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.517219
Keywords
Angiogenesis; Animal Models; Glutathionylation; Ischemia; NF-kappa B (NF-B); Redox Regulation; Vascular Endothelial Growth Factor (VEGF)
Categories
Funding
- National Institutes of Health [PO1 HL 068758, R37 HL104017, HL081587, HL007224]
- NHLBI [HHSN268201000031C]
- Department of Medicine, Boston University School of Medicine
Ask authors/readers for more resources
Background: Glutaredoxin-1 (Glrx) inhibits endothelial cell migration by reversing protein-glutathione adducts. Results: Revascularization after hind limb ischemia was inhibited in Glrx transgenic mice. Glrx overexpression increased soluble VEGF receptor 1 (sFlt) in endothelial cells via NF-B-dependent Wnt5a production. Conclusion: Glrx enhances Wnt5a-induced anti-angiogenic sFlt in endothelial cells. Significance: Up-regulated Glrx inhibits VEGF signaling by increased sFlt causing impaired vascularization. Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes, and Glrx overexpression inhibits VEGF-induced EC migration. The aim was to investigate the role of up-regulated Glrx in EC angiogenic capacities and in vivo revascularization in the setting of hind limb ischemia. Glrx-overexpressing EC from Glrx transgenic (TG) mice showed impaired migration and network formation and secreted higher levels of soluble VEGF receptor 1 (sFlt), an antagonizing factor to VEGF. After hind limb ischemia surgery Glrx TG mice demonstrated impaired blood flow recovery, associated with lower capillary density and poorer limb motor function compared with wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Noncanonical Wnt5a is known to induce sFlt. Wnt5a was highly expressed in ischemic muscles and EC from Glrx TG mice, and exogenous Wnt5a induced sFlt expression and inhibited network formation in human microvascular EC. Adenoviral Glrx-induced sFlt in EC was inhibited by a competitive Wnt5a inhibitor. Furthermore, Glrx overexpression removed GSH adducts on p65 in ischemic muscle and EC and enhanced NF-B activity, which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-B-dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt explains part of the mechanism of redox-regulated VEGF signaling.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available