Co as a Cellular Signaling Molecule

Abstract

Many biological functions of heme oxygenase (HO), such as cytoprotection against oxidative stress, vasodilation, neurotransmission in the central or peripheral nervous systems, and anti-inflammatory, anti-apoptotic, or anti-proliferative potential, have been attributed to its enzymatic byproduct carbon monoxide (CO), although roles for biliverdin/bilirubin and iron have also been proposed. In addition to these well-characterized effects, recent findings reveal that HO-derived CO may act as an oxygen sensor and circadian modulator of heme biosynthesis. In lymphocytes, CO may participate in regulatory T cell function. A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases (MAPK). Furthermore, modulation of caveolin-1 status may serve as an essential component of certain aspects of CO action, such as growth control. In this review, we summarize recent findings of the beneficial or detrimental effects of endogenous CO with an emphasis on the signaling pathways and downstream targets that trigger the action of this gas.

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…The extent of CO's effect on CLOCK(NPAS2)-BMAL1 transcriptional activity is difficult to estimate. Although CO was originally considered to be a metabolic waste product, today most of the described anti-inflammatory, antiapoptotic, antiproliferative and cytoprotective roles of heme oxygenases are ascribed to CO 35 . Owing to the affinity of CO for metal ions, the few known CO sensors are heme-containing proteins including hemoglobin, myoglobin, soluble guanylyl cyclase (sGC), cytochrome c oxidase and the transcription factors Bach-1, Bach-2 and NPAS2.…”

Placental expression profiling in preeclampsia: local overproduction of hemoglobin may drive pathological changes

“…This may lead to impaired heme degradation and contribute to the build-up of heme in the placenta. Furthermore, reduced production of carbon monoxide from heme by HO may contribute to increased vascular tone and reduced placental blood flow (46).…”

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

“…HO-1 catalyzes the rate-limiting step in the oxidative degradation of heme to equimolar quantities of biliverdin, ferrous iron, and carbon monoxide (CO). In contrast to HO-2 and HO-3, which are constitutively expressed, HO-1 is inducible and is well known to protect from cell death, i.e., apoptosis, inflammation, and oxidative stress in vivo (Otterbein et al, 2000;Deshane et al, 2005;Kim et al, 2006). A connection between HO-1 induction and the S1P pathway was recently established in a model of hepatic ischemia-reperfusion injury, where the S1P receptor agonist FTY720 enhanced HO-1 expression in hepatocytes (Man et al, 2005).…”