Activation of NAD(P)H oxidase by lipid hydroperoxides: Mechanism of oxidant-mediated smooth muscle cytotoxicity

Wei Gen Li, Lynn L. Stoll, James B. Rice, Shao Ping Xu, Francis J. Miller, Papri Chatterjee, Ling Hu, Larry W. Oberley, Arthur A. Spector, Neal L. Weintraub

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Oxidized lipids, such as 13-hydroperoxyoctadecadienoic acid (13-HPODE), have been implicated in the pathogenesis of atherosclerosis. 13-HPODE, a constituent of oxidized low-density lipoproteins, can induce cytotoxicity of vascular smooth muscle cells (SMC), which may facilitate plaque destabilization and/or rupture. 13-HPODE-induced cytotoxicity has been linked to oxidative stress, although the mechanisms by which this occurs are unknown. In the present study, we show that 13-HPODE and 9-HPODE (10-30 μM) increased superoxide (O2•-) production and induced cytotoxicity in SMC. The 13-HPODE-induced increase in O2•- was blocked by transfecting the cells with antisense oligonucleotides against p22phox, suggesting that the O2•- was produced by NAD(P)H oxidase. Similar concentrations of the corresponding HPODE reduction products, 13-hydroxyoctadecadienoic acid (13-HODE) and 9-HODE, neither increased O2•- production nor induced cytotoxicity, while 4-hydroxy nonenal (4-HNE), an unsaturated aldehyde lipid peroxidation product, induced cytotoxicity without increasing O2•- production. Treatment with superoxide dismutase or Tiron to scavenge O2•-, or transfection with p22phox antisense oligonucleotides to inhibit O2•- production, attenuated 13-HPODE-induced cytotoxicity, but not that induced by 4-HNE. These findings suggest that activation of NAD(P)H oxidase, and production of O2•-, play an important role in lipid hydroperoxide-induced smooth muscle cytotoxicity.

Original languageEnglish (US)
Pages (from-to)937-946
Number of pages10
JournalFree Radical Biology and Medicine
Volume34
Issue number7
DOIs
StatePublished - Apr 1 2003

Keywords

  • 13-HPODE
  • Atherosclerosis
  • Free radicals
  • NAD(P)H oxidase
  • Smooth muscle cells
  • Superoxide

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Li, W. G., Stoll, L. L., Rice, J. B., Xu, S. P., Miller, F. J., Chatterjee, P., Hu, L., Oberley, L. W., Spector, A. A., & Weintraub, N. L. (2003). Activation of NAD(P)H oxidase by lipid hydroperoxides: Mechanism of oxidant-mediated smooth muscle cytotoxicity. Free Radical Biology and Medicine, 34(7), 937-946. https://doi.org/10.1016/S0891-5849(03)00032-7