title: Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration.
abstract: BACKGROUND
  Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation.
  
  
  OBJECTIVE
  To determine the role of copper transporter ATP7A in PDGF-induced VSMC migration.
  
  
  RESULTS
  Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addition, ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was observed by synchrotron-based x-ray fluorescence microscopy at neointimal VSMCs in wire injury model.
  
  
  CONCLUSIONS
  These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis.
authors.affiliation: Department of Medicine, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashino
authors.forename: Varadarajan
authors.initials: V
authors.lastname: Sudhahar
authors.forename: Norifumi
authors.initials: N
authors.lastname: Urao
authors.forename: Jin
authors.initials: J
authors.lastname: Oshikawa
authors.forename: Gin-Fu
authors.initials: GF
authors.lastname: Chen
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.forename: Lydia
authors.initials: L
authors.lastname: Finney
authors.forename: Stefan
authors.initials: S
authors.lastname: Vogt
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKinney
authors.forename: Edward B
authors.initials: EB
authors.lastname: Maryon
authors.forename: Jack H
authors.initials: JH
authors.lastname: Kaplan
authors.forename: Masuko
authors.initials: M
authors.lastname: Ushio-Fukai
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000473:pathology; D027682:Cation Transport Proteins / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D010982:Platelet-Derived Growth Factor; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C486202:Atp7a protein, rat; D000073840:Copper-Transporting ATPases