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Molecular and Cellular Biology, December 2004, p. 10703-10717, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10703-10717.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

Eric Pedruzzi,1 Cécile Guichard,1 Véronique Ollivier,1 Fathi Driss,2 Michèle Fay,1 Céline Prunet,3 Jean-Claude Marie,4 Cécile Pouzet,5 Mohammad Samadi,6 Carole Elbim,1 Yvonne O'Dowd,1 Marcelle Bens,7 Alain Vandewalle,7 Marie-Anne Gougerot-Pocidalo,1 Gérard Lizard,3,{dagger} and Eric Ogier-Denis1,{dagger}*

INSERM U479,1 INSERM U410,4 INSERM U478, Faculté de Médecine Xavier Bichat,7 Hôpital X. Bichat, Service de Biochimie Hormonale et Génétique,2 IFR02, Paris,5 LIMBP Faculté des Sciences, Université de Metz, Ile de Saulcy, Metz,6 INSERM U498 CHU du Bocage, Laboratoire de Biochimie Médicale, Dijon, France3

Received 5 August 2004/ Accepted 9 September 2004

The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca2+ oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH2-terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.

* Corresponding author. Mailing address: INSERM U479, Faculté de Médecine Xavier Bichat, BP416, 75870 Paris Cedex 18, France. Phone: 33-1-44-85-62-12. Fax: 33-1-44-85-62-07. E-mail: ogier{at}bichat.inserm.fr.

{dagger} G.L. and E.O.-D. contributed equally to this study.

Molecular and Cellular Biology, December 2004, p. 10703-10717, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10703-10717.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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