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

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 microM) 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.

• Authors: Wei-Gen Li, Lynn L Stoll, James B Rice, Shao-Ping Xu, Francis J Miller Jr, Papri Chatterjee, Ling Hu, Larry W Oberley, Arthur A Spector, Neal L Weintraub
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 34 Issue 7 Pg. 937-46 (Apr 01 2003) ISSN: 0891-5849 [Print] United States
• PMID: 12654483 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Free Radicals
• Imidazoles
• Linoleic Acids
• Lipid Peroxides
• Membrane Transport Proteins
• Oligonucleotides, Antisense
• Oxidants
• Phosphoproteins
• Pyrazines
• RNA, Messenger
• Superoxides
• 13-hydroperoxy-9,11-octadecadienoic acid
• coelenterazine
• 9-hydroperoxy-11,12-octadecadienoic acid
• NADPH Oxidases
• CYBA protein, human
• NADPH Dehydrogenase
• Oxygen

Topics

• Animals
• Arteriosclerosis
• Cell Survival
• Cells, Cultured
• Enzyme Activation
• Free Radicals
• Imidazoles
• Linoleic Acids (pharmacology)
• Lipid Peroxides (metabolism, pharmacology)
• Male
• Membrane Transport Proteins
• Microscopy, Confocal
• Muscle, Smooth (cytology, metabolism)
• NADPH Dehydrogenase (metabolism)
• NADPH Oxidases (metabolism)
• Oligonucleotides, Antisense (pharmacology)
• Oxidants (metabolism)
• Oxidative Stress
• Oxygen (metabolism)
• Phosphoproteins (metabolism)
• Pyrazines (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Superoxides (metabolism)
• Transfection