Abstract
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.
Highlights
HO-1,1 the limiting step enzyme in heme degradation, is strongly involved in the control of smooth muscle proliferation [1]
We show that a recently identified carbon monoxide-releasing molecule, [Ru(CO)3Cl2]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
The main results of this study are that carbon monoxide-releasing molecules (CORMs)-2, a carbon monoxide-releasing molecule 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 [35]
Summary
HO-1,1 the limiting step enzyme in heme degradation, is strongly involved in the control of smooth muscle proliferation [1]. The specific pathway responsible for cyclin D1 expression is sensitive to oxidants [10] In view of these findings, the existence of a potential “CO sensor” that regulates ASMC proliferation cannot be excluded a priori and represents a challenging hypothesis to explore further. Two important sources of oxidants involved in the control of cell proliferation are the NAD(P)H oxidase [11, 12] and the mitochondrial respiratory chain [13,14,15,16]. Inhibition of electron transfer in the mitochondrial respiratory chain is associated with a significant increase in the production of superoxide anion and hydrogen peroxide and a decreased cell proliferation [14, 16]. Cytochrome b558 of the NAD(P)H oxidase and/or cytochromes of the respiratory chain, affecting redox-mediated cell proliferation
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