Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization

Dong Hoon Kang, Doo Jae Lee, Jiran Kim, Joo Young Lee, Hyun Woo Kim, Kihwan Kwon, W. Robert Taylor, Hanjoong Jo, Sang Won Kang

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

BACKGROUND - : Typical 2-Cys peroxiredoxin (Prx) is inactivated by overoxidation of the peroxidatic cysteine residue under oxidative stress. However, the significance in the context of vascular disease is unknown. METHODS AND RESULTS - : Immunohistochemical analyses revealed that 2-Cys Prxs, particularly Prx type II, are heavily overoxidized in balloon-injured rodent carotid vessels and in human atherosclerotic lesions. Consistent with this observation, the selective depletion of Prx II exacerbated neointimal hyperplasia in injured carotid vessels. We also found that the epipolythiodioxopiperazine class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H2O2 in the vascular cells. Functionally, the epipolythiodioxopiperazines reciprocally regulated the platelet-derived growth factor receptor-β- and vascular endothelial growth factor receptor-mediated signaling in these vascular cells by replacing Prx II. As a consequence, the epipolythiodioxopiperazines inhibited the proliferative and migratory activities of smooth muscle cells but promoted those of endothelial cells in vitro. Moreover, administration of the epipolythiodioxopiperazines to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialization. CONCLUSIONS - : This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and thus the therapeutic use of their activity mimetic in vascular injuries like stenting.

Original languageEnglish
Pages (from-to)834-844
Number of pages11
JournalCirculation
Volume128
Issue number8
DOIs
StatePublished - 20 Aug 2013

Keywords

  • coronary restenosis
  • endothelium
  • peroxiredoxins
  • reactive oxygen species
  • receptor protein-tyrosine kinases

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