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J. Biol. Chem., Vol. 280, Issue 27, 25350-25360, July 8, 2005

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Mitochondrial Respiratory Chain and NAD(P)H Oxidase Are Targets for the Antiproliferative Effect of Carbon Monoxide in Human Airway Smooth Muscle^*

Camille Taillé, Jamel El-Benna, Sophie Lanone, Jorge Boczkowski¶, and Roberto Motterlini||

From the INSERM Unité 700 and Unité 683, Institut Fédératif de Recherche 02, Faculté de Médecine Xavier Bichat, 75018 Paris, France and the^|| Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, United Kingdom

Carbon monoxide (CO), one of the end products of heme oxygenase activity, inhibits smooth muscle proliferation by decreasing ERK1/2 phosphorylation and cyclin D1 expression, a signaling pathway that is known to be modulated by reactive oxygen species (ROS) in airway smooth muscle cells (ASMCs). Two important sources of ROS involved in cell signaling are the membrane NAD(P)H oxidase and the mitochondrial respiratory chain. Thus, that CO could modulate redox signaling in ASMCs by interacting with the heme moiety of NAD(P)H oxidase and/or the respiratory chain is a plausible hypothesis. Here we show that a recently identified carbon monoxide-releasing molecule, [Ru(CO)₃Cl₂]₂ (or CORM-2) 1) inhibits NAD(P)H oxidase cytochrome b₅₅₈ activity, 2) increases oxidant production by the mitochondria, and 3) inhibits ASMC proliferation and phosphorylation of the ERK1/2 mitogen-activated protein kinase and expression of cyclin D1, two critical pathways involved in muscle proliferation. No such effects were observed with the negative control (Ru(Me₂SO)₄Cl₂), which does not contain CO groups. Because both diphenylene iodinium or apocynin (inhibitors of NAD(P)H oxidase) and rotenone (a molecule that increases mitochondrial ROS production by blocking the respiratory chain) mimicked the effect of CORM-2 on cyclin D1 expression and ASMC proliferation, the antiproliferative effect of CORM-2 is probably related to inhibition of cytochromes on both NAD(P)H oxidase and the respiratory chain. The involvement of increased mitochondria-derived oxidants is substantiated by the findings showing that the antioxidant N-acetylcysteine partially inhibited the effects of CORM-2. This study provides a new mechanism to explain redox signaling by CO.

Received for publication, March 31, 2005

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: INSERM, Unité 700, Faculté deMédecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. Tel.: 33-1-44-85-62-50; Fax: 33-1-42-26-33-30; E-mail: jbb2{at}bichat.inserm.fr.

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