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 articlepeer-review

    32 Citations (Scopus)
    236 Downloads (Pure)

    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

    Keywords

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

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