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

doi:10.1016/S0891-5849(03)00032-7

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

Cardiology

Research output: Contribution to journal › Article › peer-review

48 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 p22^phox, 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 p22^phox 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 language	English (US)
Pages (from-to)	937-946
Number of pages	10
Journal	Free Radical Biology and Medicine
Volume	34
Issue number	7
DOIs	https://doi.org/10.1016/S0891-5849(03)00032-7
State	Published - 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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10.1016/S0891-5849(03)00032-7

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@article{44595a2404274740be6dbf894e1573a8,

title = "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 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.",

keywords = "13-HPODE, Atherosclerosis, Free radicals, NAD(P)H oxidase, Smooth muscle cells, Superoxide",

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

note = "Funding Information: We thank G. R. Aylsworth and P. Q. Wang for their technical assistance. This work was supported by National Institutes of Health grants HL49264 and HL62984 (to A.A.S., N.L.W., and F.J.M.), and CA66081 (to L.W.O.), and by a Grant-in-Aid from the American Heart Association, Heartland Affiliate to W.G.L.",

year = "2003",

month = apr,

day = "1",

doi = "10.1016/S0891-5849(03)00032-7",

language = "English (US)",

volume = "34",

pages = "937--946",

journal = "Free Radical Biology and Medicine",

issn = "0891-5849",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Activation of NAD(P)H oxidase by lipid hydroperoxides

T2 - Mechanism of oxidant-mediated smooth muscle cytotoxicity

AU - Li, Wei Gen

AU - Stoll, Lynn L.

AU - Rice, James B.

AU - Xu, Shao Ping

AU - Miller, Francis J.

AU - Chatterjee, Papri

AU - Hu, Ling

AU - Oberley, Larry W.

AU - Spector, Arthur A.

AU - Weintraub, Neal L.

N1 - Funding Information: We thank G. R. Aylsworth and P. Q. Wang for their technical assistance. This work was supported by National Institutes of Health grants HL49264 and HL62984 (to A.A.S., N.L.W., and F.J.M.), and CA66081 (to L.W.O.), and by a Grant-in-Aid from the American Heart Association, Heartland Affiliate to W.G.L.

PY - 2003/4/1

Y1 - 2003/4/1

N2 - 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.

AB - 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.

KW - 13-HPODE

KW - Atherosclerosis

KW - Free radicals

KW - NAD(P)H oxidase

KW - Smooth muscle cells

KW - Superoxide

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SN - 0891-5849

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JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

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ER -

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

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