Participation of ATP7A in macrophage mediated oxidation of LDL

Zhenyu Qin, Eddy S. Konaniah, Bonnie Neltner, Raphael A. Nemenoff, David Y. Hui, Neal Lee Weintraub

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

ATP7A primarily functions to egress copper from cells, thereby supplying this cofactor to secreted copper-accepting enzymes. This ATPase has attracted significant attention since the discovery of its mutation leading to human Menkes disease and the demonstration of its distribution in various tissues. Recently, we reported that ATP7A is expressed in the human vasculature. In the present study, we investigated the cellular expression of ATP7A in atherosclerotic lesions of LDL receptor -/- mice. Subsequently, we examined the role of ATP7A in regulating the oxidation of LDL in a macrophage cell model. We observed that ATP7A is expressed in atherosclerotic murine aorta and colocalizes with macrophages. To investigate the function of ATP7A, we downregulated ATP7A expression in THP-1 derived macrophages using small interfering RNA ( siRNA). ATP7A downregulation attenuated cell-mediated oxidation of LDL. Moreover, downregulation of ATP7A resulted in decreased expression and enzymatic activity of cytosolic phospholipase A2 α (cPLA2α), a key intracellular enzyme involved in cell-mediated LDL oxidation. In addition, cPLA2α promoter activity was decreased after downregulation of ATP7A, suggesting that ATP7A transcriptionally regulates cPLA2α expression. Finally, cPLA2α overexpression increased LDL oxidation, which was blocked by coadministration of ATP7A siRNA oligonucleotides. These findings suggest a novel mechanism linking ATP7A to cPLA2α and LDL oxidation, suggesting that this copper transporter could play a previously unrecognized role in the pathogenesis of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)1471-1477
Number of pages7
JournalJournal of Lipid Research
Volume51
Issue number6
DOIs
StatePublished - Jun 1 2010

Fingerprint

Cytosolic Phospholipases A2
Macrophages
Down-Regulation
Oxidation
Copper
Small Interfering RNA
Menkes Kinky Hair Syndrome
LDL Receptors
Enzymes
Oligonucleotides
Adenosine Triphosphatases
Aorta
Atherosclerosis
Demonstrations
oxidized low density lipoprotein
Tissue
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Qin, Z., Konaniah, E. S., Neltner, B., Nemenoff, R. A., Hui, D. Y., & Weintraub, N. L. (2010). Participation of ATP7A in macrophage mediated oxidation of LDL. Journal of Lipid Research, 51(6), 1471-1477. https://doi.org/10.1194/jlr.M003426

Participation of ATP7A in macrophage mediated oxidation of LDL. / Qin, Zhenyu; Konaniah, Eddy S.; Neltner, Bonnie; Nemenoff, Raphael A.; Hui, David Y.; Weintraub, Neal Lee.

In: Journal of Lipid Research, Vol. 51, No. 6, 01.06.2010, p. 1471-1477.

Research output: Contribution to journalArticle

Qin, Z, Konaniah, ES, Neltner, B, Nemenoff, RA, Hui, DY & Weintraub, NL 2010, 'Participation of ATP7A in macrophage mediated oxidation of LDL', Journal of Lipid Research, vol. 51, no. 6, pp. 1471-1477. https://doi.org/10.1194/jlr.M003426
Qin, Zhenyu ; Konaniah, Eddy S. ; Neltner, Bonnie ; Nemenoff, Raphael A. ; Hui, David Y. ; Weintraub, Neal Lee. / Participation of ATP7A in macrophage mediated oxidation of LDL. In: Journal of Lipid Research. 2010 ; Vol. 51, No. 6. pp. 1471-1477.
@article{d6cdae18af99498eaeea1ecd306957b1,
title = "Participation of ATP7A in macrophage mediated oxidation of LDL",
abstract = "ATP7A primarily functions to egress copper from cells, thereby supplying this cofactor to secreted copper-accepting enzymes. This ATPase has attracted significant attention since the discovery of its mutation leading to human Menkes disease and the demonstration of its distribution in various tissues. Recently, we reported that ATP7A is expressed in the human vasculature. In the present study, we investigated the cellular expression of ATP7A in atherosclerotic lesions of LDL receptor -/- mice. Subsequently, we examined the role of ATP7A in regulating the oxidation of LDL in a macrophage cell model. We observed that ATP7A is expressed in atherosclerotic murine aorta and colocalizes with macrophages. To investigate the function of ATP7A, we downregulated ATP7A expression in THP-1 derived macrophages using small interfering RNA ( siRNA). ATP7A downregulation attenuated cell-mediated oxidation of LDL. Moreover, downregulation of ATP7A resulted in decreased expression and enzymatic activity of cytosolic phospholipase A2 α (cPLA2α), a key intracellular enzyme involved in cell-mediated LDL oxidation. In addition, cPLA2α promoter activity was decreased after downregulation of ATP7A, suggesting that ATP7A transcriptionally regulates cPLA2α expression. Finally, cPLA2α overexpression increased LDL oxidation, which was blocked by coadministration of ATP7A siRNA oligonucleotides. These findings suggest a novel mechanism linking ATP7A to cPLA2α and LDL oxidation, suggesting that this copper transporter could play a previously unrecognized role in the pathogenesis of atherosclerosis.",
author = "Zhenyu Qin and Konaniah, {Eddy S.} and Bonnie Neltner and Nemenoff, {Raphael A.} and Hui, {David Y.} and Weintraub, {Neal Lee}",
year = "2010",
month = "6",
day = "1",
doi = "10.1194/jlr.M003426",
language = "English (US)",
volume = "51",
pages = "1471--1477",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Participation of ATP7A in macrophage mediated oxidation of LDL

AU - Qin, Zhenyu

AU - Konaniah, Eddy S.

AU - Neltner, Bonnie

AU - Nemenoff, Raphael A.

AU - Hui, David Y.

AU - Weintraub, Neal Lee

PY - 2010/6/1

Y1 - 2010/6/1

N2 - ATP7A primarily functions to egress copper from cells, thereby supplying this cofactor to secreted copper-accepting enzymes. This ATPase has attracted significant attention since the discovery of its mutation leading to human Menkes disease and the demonstration of its distribution in various tissues. Recently, we reported that ATP7A is expressed in the human vasculature. In the present study, we investigated the cellular expression of ATP7A in atherosclerotic lesions of LDL receptor -/- mice. Subsequently, we examined the role of ATP7A in regulating the oxidation of LDL in a macrophage cell model. We observed that ATP7A is expressed in atherosclerotic murine aorta and colocalizes with macrophages. To investigate the function of ATP7A, we downregulated ATP7A expression in THP-1 derived macrophages using small interfering RNA ( siRNA). ATP7A downregulation attenuated cell-mediated oxidation of LDL. Moreover, downregulation of ATP7A resulted in decreased expression and enzymatic activity of cytosolic phospholipase A2 α (cPLA2α), a key intracellular enzyme involved in cell-mediated LDL oxidation. In addition, cPLA2α promoter activity was decreased after downregulation of ATP7A, suggesting that ATP7A transcriptionally regulates cPLA2α expression. Finally, cPLA2α overexpression increased LDL oxidation, which was blocked by coadministration of ATP7A siRNA oligonucleotides. These findings suggest a novel mechanism linking ATP7A to cPLA2α and LDL oxidation, suggesting that this copper transporter could play a previously unrecognized role in the pathogenesis of atherosclerosis.

AB - ATP7A primarily functions to egress copper from cells, thereby supplying this cofactor to secreted copper-accepting enzymes. This ATPase has attracted significant attention since the discovery of its mutation leading to human Menkes disease and the demonstration of its distribution in various tissues. Recently, we reported that ATP7A is expressed in the human vasculature. In the present study, we investigated the cellular expression of ATP7A in atherosclerotic lesions of LDL receptor -/- mice. Subsequently, we examined the role of ATP7A in regulating the oxidation of LDL in a macrophage cell model. We observed that ATP7A is expressed in atherosclerotic murine aorta and colocalizes with macrophages. To investigate the function of ATP7A, we downregulated ATP7A expression in THP-1 derived macrophages using small interfering RNA ( siRNA). ATP7A downregulation attenuated cell-mediated oxidation of LDL. Moreover, downregulation of ATP7A resulted in decreased expression and enzymatic activity of cytosolic phospholipase A2 α (cPLA2α), a key intracellular enzyme involved in cell-mediated LDL oxidation. In addition, cPLA2α promoter activity was decreased after downregulation of ATP7A, suggesting that ATP7A transcriptionally regulates cPLA2α expression. Finally, cPLA2α overexpression increased LDL oxidation, which was blocked by coadministration of ATP7A siRNA oligonucleotides. These findings suggest a novel mechanism linking ATP7A to cPLA2α and LDL oxidation, suggesting that this copper transporter could play a previously unrecognized role in the pathogenesis of atherosclerosis.

UR - http://www.scopus.com/inward/record.url?scp=77952710232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952710232&partnerID=8YFLogxK

U2 - 10.1194/jlr.M003426

DO - 10.1194/jlr.M003426

M3 - Article

VL - 51

SP - 1471

EP - 1477

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 6

ER -