Participation of ATP7A in macrophage mediated oxidation of LDL

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

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11 Scopus citations

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
Publication statusPublished - Jun 1 2010
Externally publishedYes

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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