Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration

Takashi Ashino, Varadarajan Sudhahar, Norifumi Urao, Jin Oshikawa, Gin Fu Chen, Huan Wang, Yuqing Huo, Lydia Finney, Stefan Vogt, Ronald D. McKinney, Edward B. Maryon, Jack H. Kaplan, Masuko Ushio-Fukai, Tohru Fukai

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Rationale: 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)787-799
Number of pages13
JournalCirculation research
Volume107
Issue number6
DOIs
StatePublished - Sep 17 2010

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Platelet-Derived Growth Factor
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Movement
Copper
trans-Golgi Network
Lipids
Small Interfering RNA
Atherosclerosis
Platelet-Derived Growth Factor Receptors
Enzyme Precursors
Synchrotrons
Pseudopodia
Vascular System Injuries
Wounds and Injuries
Fluorescence Microscopy
Biological Availability
Adenosine Triphosphatases
Oxidoreductases
X-Rays

Keywords

  • copper transporter
  • migration
  • platelet-derived growth factor
  • vascular remodeling
  • vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration. / Ashino, Takashi; Sudhahar, Varadarajan; Urao, Norifumi; Oshikawa, Jin; Chen, Gin Fu; Wang, Huan; Huo, Yuqing; Finney, Lydia; Vogt, Stefan; McKinney, Ronald D.; Maryon, Edward B.; Kaplan, Jack H.; Ushio-Fukai, Masuko; Fukai, Tohru.

In: Circulation research, Vol. 107, No. 6, 17.09.2010, p. 787-799.

Research output: Contribution to journalArticle

Ashino, T, Sudhahar, V, Urao, N, Oshikawa, J, Chen, GF, Wang, H, Huo, Y, Finney, L, Vogt, S, McKinney, RD, Maryon, EB, Kaplan, JH, Ushio-Fukai, M & Fukai, T 2010, 'Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration', Circulation research, vol. 107, no. 6, pp. 787-799. https://doi.org/10.1161/CIRCRESAHA.110.225334
Ashino, Takashi ; Sudhahar, Varadarajan ; Urao, Norifumi ; Oshikawa, Jin ; Chen, Gin Fu ; Wang, Huan ; Huo, Yuqing ; Finney, Lydia ; Vogt, Stefan ; McKinney, Ronald D. ; Maryon, Edward B. ; Kaplan, Jack H. ; Ushio-Fukai, Masuko ; Fukai, Tohru. / Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration. In: Circulation research. 2010 ; Vol. 107, No. 6. pp. 787-799.
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abstract = "Rationale: 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. Methods and 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.",
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AU - Ashino, Takashi

AU - Sudhahar, Varadarajan

AU - Urao, Norifumi

AU - Oshikawa, Jin

AU - Chen, Gin Fu

AU - Wang, Huan

AU - Huo, Yuqing

AU - Finney, Lydia

AU - Vogt, Stefan

AU - McKinney, Ronald D.

AU - Maryon, Edward B.

AU - Kaplan, Jack H.

AU - Ushio-Fukai, Masuko

AU - Fukai, Tohru

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N2 - Rationale: 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. Methods and 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.

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KW - migration

KW - platelet-derived growth factor

KW - vascular remodeling

KW - vascular smooth muscle

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