Heme oxygenase and carbon monoxide initiate homeostatic signaling

Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. Many biological functions of HO, such as regulation of vessel tone, smooth muscle cell proliferation, neurotransmission, and platelet aggregation, and anti-inflammatory and antiapoptotic effects have been attributed to its enzymatic product, CO. How can such diverse actions be achieved by a simple diatomic gas; can its protective effects be explained via regulation of a common signaling pathway? A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases. The consequences of this activation remain unknown but appear to differ depending on cell type and circumstances. The majority of studies reporting a protective role of CO focus on pathways initiated by the pathological stimulus (e.g., lipopolysaccharide, hypoxia, balloon injury, tumor necrosis factor alpha, etc.) and its consequential modulation by CO. What has been less studied is the manner in which CO exposure alone modulates the molecular machinery of the cell so that a subsequent stress stimulus will elicit a homeostatic response as opposed to one that is chaotic and disordered. CO potentially interacts with other intracellular hemoprotein targets, although little is known about the functional significance of such interactions other then the known targets including mitochondrial oxidases, oxygen sensors, and nitric oxide synthases. The earliest response of a cell exposed to low concentrations of CO is clearly an increase in reactive oxygen species formation that we define as oxidative conditioning. This has important consequences for inflammation, proliferation, mitochondria biogenesis, and apoptosis. Within this review, we will highlight recent research on the molecular events underlying the physiologic effects of CO-which lead to cytoprotective conditioning.