Novel role of copper transport protein antioxidant-1 in neointimal formation after vascular injury

Takashi Kohno, Norifumi Urao, Takashi Ashino, Varadarajan Sudhahar, Ronald D. McKinney, Takao Hamakubo, Hiroko Iwanari, Masuko Ushio-Fukai, Tohru Fukai

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

OBJECTIVE: Vascular smooth muscle cell (VSMC) migration is critically important for neointimal formation after vascular injury and atherosclerosis lesion formation. Copper (Cu) chelator inhibits neointimal formation, and we previously demonstrated that Cu transport protein antioxidant-1 (Atox1) is involved in Cu-induced cell growth. However, role of Atox1 in VSMC migration and neointimal formation after vascular injury is unknown. APPROACH AND RESULTS: Here, we show that Atox1 expression is upregulated in injured vessel, and it is colocalized with the Cu transporter ATP7A, one of the downstream targets of Atox1, mainly in neointimal VSMCs at day 14 after wire injury. Atox1 mice show inhibition of neointimal formation and extracellular matrix expansion, which is associated with a decreased VSMCs accumulation within neointima and lysyl oxidase activity. Mechanistically, in cultured VSMC, Atox1 depletion with siRNA inhibits platelet-derived growth factor-induced Cu-dependent VSMC migration by preventing translocation of ATP7A and small G protein Rac1 to the leading edge, as well as Cu- and Rac1-dependent lamellipodia formation. Furthermore, Atox1 mice show decreased perivascular macrophage infiltration in wire-injured vessels, as well as thioglycollate-induced peritoneal macrophage recruitment. CONCLUSIONS: Atox1 is involved in neointimal formation after vascular injury through promoting VSMC migration and inflammatory cell recruitment in injured vessels. Thus, Atox1 is a potential therapeutic target for VSMC migration and inflammation-related vascular diseases.

Original languageEnglish (US)
Pages (from-to)805-813
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number4
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

Keywords

  • ATP7A
  • antioxidant-1
  • copper transport protein
  • migration
  • platelet-derived growth factor
  • vascular injury
  • vascular smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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