Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization

Colin E. Murdoch, Michaela Shuler, Dagmar J.F. Haeussler, Ryosuke Kikuchi, Priyanka Bearelly, Jingyan Han, Yosuke Watanabe, José J. Fuster, Kenneth Walsh, Ye-Shih Ho, Markus M. Bachschmid, Richard A. Cohen, Reiko Matsui

Research output: Contribution to journalArticle

Abstract

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. Glrx overexpression inhibits VEGF-induced endothelial cell (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 mice (TG) showed impaired migration and network formation and secreted higher level 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 to wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Non-canonical 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 nuclear factor kappa B (NF-kB) activity which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-kB -dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt may be a part of mechanism of redox regulated VEGF signaling.
Original languageEnglish
Pages (from-to)8633-8644
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number12
Early online date30 Jan 2014
DOIs
Publication statusPublished - 21 Mar 2014

Fingerprint

Glutaredoxins
Vascular Endothelial Growth Factor Receptor-1
Up-Regulation
Ischemia
Extremities
Endothelial cells
Endothelial Cells
Transgenic Mice
Vascular Endothelial Growth Factor A
Muscle
NF-kappa B
Muscle Cells
Surgery
Vascular Endothelial Growth Factor Receptor
Protein S
Medical problems

Bibliographical note

This research was originally published in Journal of Biological Chemistry. Murdoch, Colin E.; Shuler, Michaela; Haeussler, Dagmar J.F.; Kikuchi, Ryosuke; Bearelly, Priyanka; Han, Jingyan; Watanabe, Yosuke; Fuster, José J.; Walsh, Kenneth; Ho, Ye-Shih; Bachschmid, Markus M.; Cohen, Richard A.; Matsui, Reiko. Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. Journal of biological chemistry. 2014; 289:8633-8644. © the American Society for Biochemistry and Molecular Biology.

Funding: National Institutes of Health Grants PO1 HL 068758, R37 HL104017, and NHLBI contract number HHSN268201000031C (RAC), and HL081587 (KW).

Keywords

  • angiogenesis
  • animal models
  • glutathionylation
  • ischemia
  • NF-kappa B (NF-KB)
  • Redox regulation
  • vascular endothelial growth factor

Cite this

Murdoch, Colin E. ; Shuler, Michaela ; Haeussler, Dagmar J.F. ; Kikuchi, Ryosuke ; Bearelly, Priyanka ; Han, Jingyan ; Watanabe, Yosuke ; Fuster, José J. ; Walsh, Kenneth ; Ho, Ye-Shih ; Bachschmid, Markus M. ; Cohen, Richard A. ; Matsui, Reiko. / Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 12. pp. 8633-8644.
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abstract = "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. Glrx overexpression inhibits VEGF-induced endothelial cell (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 mice (TG) showed impaired migration and network formation and secreted higher level 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 to wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Non-canonical 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 nuclear factor kappa B (NF-kB) activity which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-kB -dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt may be a part of mechanism of redox regulated VEGF signaling.",
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Murdoch, CE, Shuler, M, Haeussler, DJF, Kikuchi, R, Bearelly, P, Han, J, Watanabe, Y, Fuster, JJ, Walsh, K, Ho, Y-S, Bachschmid, MM, Cohen, RA & Matsui, R 2014, 'Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization', Journal of Biological Chemistry, vol. 289, no. 12, pp. 8633-8644. https://doi.org/10.1074/jbc.M113.517219

Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. / Murdoch, Colin E.; Shuler, Michaela; Haeussler, Dagmar J.F.; Kikuchi, Ryosuke; Bearelly, Priyanka; Han, Jingyan; Watanabe, Yosuke; Fuster, José J.; Walsh, Kenneth; Ho, Ye-Shih; Bachschmid, Markus M.; Cohen, Richard A.; Matsui, Reiko.

In: Journal of Biological Chemistry, Vol. 289, No. 12, 21.03.2014, p. 8633-8644.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization

AU - Murdoch, Colin E.

AU - Shuler, Michaela

AU - Haeussler, Dagmar J.F.

AU - Kikuchi, Ryosuke

AU - Bearelly, Priyanka

AU - Han, Jingyan

AU - Watanabe, Yosuke

AU - Fuster, José J.

AU - Walsh, Kenneth

AU - Ho, Ye-Shih

AU - Bachschmid, Markus M.

AU - Cohen, Richard A.

AU - Matsui, Reiko

N1 - This research was originally published in Journal of Biological Chemistry. Murdoch, Colin E.; Shuler, Michaela; Haeussler, Dagmar J.F.; Kikuchi, Ryosuke; Bearelly, Priyanka; Han, Jingyan; Watanabe, Yosuke; Fuster, José J.; Walsh, Kenneth; Ho, Ye-Shih; Bachschmid, Markus M.; Cohen, Richard A.; Matsui, Reiko. Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. Journal of biological chemistry. 2014; 289:8633-8644. © the American Society for Biochemistry and Molecular Biology. Funding: National Institutes of Health Grants PO1 HL 068758, R37 HL104017, and NHLBI contract number HHSN268201000031C (RAC), and HL081587 (KW).

PY - 2014/3/21

Y1 - 2014/3/21

N2 - 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. Glrx overexpression inhibits VEGF-induced endothelial cell (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 mice (TG) showed impaired migration and network formation and secreted higher level 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 to wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Non-canonical 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 nuclear factor kappa B (NF-kB) activity which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-kB -dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt may be a part of mechanism of redox regulated VEGF signaling.

AB - 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. Glrx overexpression inhibits VEGF-induced endothelial cell (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 mice (TG) showed impaired migration and network formation and secreted higher level 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 to wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Non-canonical 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 nuclear factor kappa B (NF-kB) activity which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-kB -dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt may be a part of mechanism of redox regulated VEGF signaling.

KW - angiogenesis

KW - animal models

KW - glutathionylation

KW - ischemia

KW - NF-kappa B (NF-KB)

KW - Redox regulation

KW - vascular endothelial growth factor

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DO - 10.1074/jbc.M113.517219

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VL - 289

SP - 8633

EP - 8644

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

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