Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance.
Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. HO exists as constitutive (HO-2, HO-3) and inducible isoforms (HO-1), the latter which responds to regulation by multiple stress-stimuli. HO-1 confers protection in vitro and in vivo against oxidative cellular stress. Although the redox active compounds that are generated from HO activity (i.e. iron, biliverdin-IXalpha, and bilirubin-IXa) potentially modulate oxidative stress resistance, increasing evidence points to cytoprotective roles for CO. Though not reactive, CO regulates vascular processes such as vessel tone, smooth muscle proliferation, and platelet aggregation, and possibly functions as a neurotransmitter. The latter effects of CO depend on the activation of guanylate cyclase activity by direct binding to the heme moiety of the enzyme, stimulating the production of cyclic 3':5'-guanosine monophosphate. CO potentially interacts with other intracellular hemoprotein targets, though little is known about the functional significance of such interactions. Recent progress indicates that CO exerts novel anti-inflammatory and anti-apoptotic effects dependent on the modulation of the p38 mitogen activated protein kinase (MAPK)-signaling pathway. By virtue of these effects, CO confers protection in oxidative lung injury models, and likely plays a role in HO-1 mediated tissue protection.
Ryter
Stefan W
SW
Department of Medicine, University of Pittsburgh Medical Center, PA 15213, USA. Ryters@msx.upmc.edu
Otterbein
Leo E
LE
Morse
Danielle
D
Choi
Augustine M K
AM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction; D013312:Stress, Physiological / Q000201:enzymology
D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)