Redox regulation of ischemic limb neovascularization - What we have learned from animal studies

Reiko Matsui, Yosuke Watanabe, Colin E. Murdoch

Research output: Contribution to journalReview article

Abstract

Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.

Original languageEnglish
Pages (from-to)1011-1019
Number of pages9
JournalRedox biology
Volume12
Early online date4 May 2017
DOIs
Publication statusPublished - Aug 2017

Fingerprint

Glutaredoxins
Oxidants
Oxidation-Reduction
Animals
Extremities
Muscle
Antioxidants
Cell signaling
Muscles
Peripheral Arterial Disease
Femoral Artery
Transcription
Hindlimb
Medical problems
Sulfhydryl Compounds
Vascular Endothelial Growth Factor A
Glutathione
Cysteine
Atherosclerosis
Ischemia

Bibliographical note

© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Keywords

  • ischemic limb
  • angiogenesis
  • oxidants
  • GSH adducts
  • glutaredoxin

Cite this

Matsui, Reiko ; Watanabe, Yosuke ; Murdoch, Colin E. / Redox regulation of ischemic limb neovascularization - What we have learned from animal studies. In: Redox biology. 2017 ; Vol. 12. pp. 1011-1019.
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Redox regulation of ischemic limb neovascularization - What we have learned from animal studies. / Matsui, Reiko; Watanabe, Yosuke; Murdoch, Colin E.

In: Redox biology, Vol. 12, 08.2017, p. 1011-1019.

Research output: Contribution to journalReview article

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