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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) 3 Cl 2 ] 2 (or CORM-2) 1) inhibits NAD(P)H
oxidase cytochrome b 558 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(Me 2 SO) 4 Cl 2 ), 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.