Carbon monoxide: Mechanisms of action and potential clinical implications
Introduction
The diverse physiological actions of “biological gasses”: dioxygen (O2), hydrogen disulfide (H2S), nitric oxide (NO) and carbon monoxide (CO) have attracted much interest (Wang, 2002, Ryter and Otterbein, 2004, Wu and Wang, 2005, Rochette and Vergely, 2008b, Lamon et al., 2009, Motterlini and Otterbein, 2010). The multiplicity of gas actions and gas targets associated with the difficulty in measuring local gas concentrations obscures detailed mechanisms whereby gasses exert their actions. A central question is how do these gasses interact with one another when transducing signals and modulating cell function? Among the major free radicals with essential functions in cells are reactive oxygen species (ROS) like superoxide anion (O2−), hydroxyl radical (OH) and reactive nitrogen species (RNS) such as nitric oxide (NO) (Halliwell, 2007a). It has brought into focus reactive species described by chemists but forgotten in biology. About 0.3% of O2− present in cell cytosol exists in its protonated form: hydroperoxyl radical (HO2). Water (H2O) can be split into two free radicals: OH and hydrogen radical (H). The transmembrane electrochemical potential is a major force in cellular energy production. Several free radicals, including thiyl radicals (RS) and nitrogen dioxide (NO2) are known to isomerize double bonds. Evidence is emerging that hydrogen sulfide (H2S), essentially as hydrogen thiol (H-SH), is a signaling molecule in vivo which can be a source of free radicals (Rochette & Vergely, 2008a). The Cu–Zn superoxide dismutase (SOD) enzyme can oxidize the ionized form of H2S to hydro-sulfide radical: HS. Recent studies suggest that H2S plays an important function in cardiovascular functions (Rochette and Vergely, 2008b, Whiteman and Moore, 2009). Unlike the high reactivity of NO which is a free radical, CO does not contain free electrons. It has been reported that in the cell carbonate radical anion (CO3−) may be formed after the oxidation of CO to CO2 (Kajimura et al., 2010). In this review, we will describe some functions of this radical such as its participation in the activity of Cu–Zn SOD. Carbonate radicals can be also formed when OH reacts with carbonate or bicarbonate ions. Recently, it has been reported that carbonate anion was a potentially relevant oxidant in physiological environments. In this article, we will develop the importance of CO, its interaction with free radicals and the potential medical applications of this gas molecule; two organs being particularly susceptible to CO: the heart and the brain. Our focus is on the cardiovascular effects of CO and CO-RMs (Prockop and Chichkova, 2007, Motterlini and Otterbein, 2010). In this regard, we discuss in a next part of this review why CO is an important signaling mediator possessing vasodilatory properties, which are achieved by activation of the guanylate-cyclase-cGMP pathway as well as large-conductance potassium channels (Dong et al., 2007, Wilkinson and Kemp, 2011).
Section snippets
Production of carbon monoxide and “gas-sensors”
CO is a ubiquitous air pollutant. It originates from the oxidation or combustion of organic matter, coke and tobacco. Cigarette smoke accounts for a major source of CO exposure in humans. Clinical sign of CO poisoning includes shortness of breath and headache. Lethality after CO exposure results from tissue hypoxia following hemoglobin saturation. CO diminishes the blood capacity to deliver oxygen to tissue leading to hypoxia (Wu & Wang, 2005). Small amounts of carbon monoxide (CO) are
Overview: catabolism of endogenous carbon monoxide
CO is the diatomic oxide of carbon. At temperatures above −190 °C, CO is a colorless and odorless gas. The specific gravity of CO is 0.967 relative to air, and its density is 1.25 g/L at standard temperature and pressure. CO is a chemically stable molecule because of its formal triple bond. Chemical reduction of CO requires temperatures well above 100 °C. The water solubility of CO is very low at standard temperature and pressure. CO cannot react with water without substantial energy input. Even
Heme-oxygenase and cellular metabolism
HO-1 mediates the degradation of free and protein-bound heme, and promotes the formation of protective compounds. Numerous studies have indicated that HO-1 induction is an adaptive defense mechanism to protect cells and tissues against injury in many disease settings. Given that inflammation and oxidative stress are associated with the development of cardiovascular disease and that HO-1 has anti-inflammatory and anti-oxidative properties, HO-1 is emerging as a great potential therapeutic target
Carbonate radical anion (CO3−) production and interaction with endogenous compounds (Fig. 5)
Bicarbonate anion (HCO3−) is present in high concentrations (25 mM) in biological tissues. The role of bicarbonate anion in biological oxidation has largely been ignored. The relationship between the metabolism of carbonate and ROS has been recently studied in particular concerning the activity of antioxidant enzymes. A new perspective on the role of bicarbonate anion in SOD1-catalyzed peroxidative reactions was recently proposed. The copper-bound oxidant (Cu2+-OH) could oxidize HCO3− to the
Signaling to heme-oxygenase-1
The induction of HO-1 expression is an important aspect of the anti-inflammatory, anti-apoptotic response to cellular stress. The gene coding for HO-1 is highly regulated, and in most cell types, HO-1 is expressed in response to numerous stimuli (Kim et al., 2006, Ryter et al., 2006). Regulation of the HO-1 gene is predominantly at the transcriptional level. Various transcription factors will interact with DNA binding domains in the HO-1 promoter to regulate gene transcription. A number of
Carbon monoxide-releasing molecules (CO-RMs) and carbon monoxide gas
The development of a technology that controls the delivery of CO under different physiological conditions represents a major step in the use of CO-RMs. There is an abundance of preclinical evidence in experimental studies showing the beneficial effects of CO, administered as a gas or as a CO-RM, in cardiovascular disease (Ryter et al., 2006, Motterlini, 2007). CORM-3 and CORM-A1 represent the examples of water-soluble CO releasers (Fig. 2). As we reported previously, the two compounds are
Summary and future directions
There are still a number of questions that remain to be answered, especially in relation to the interactions between the gasses such as CO and NO or H2S. For instance, the exact correlation between these gasses in the various pathways of cytoprotection has yet to be fully investigated (Kajimura et al., 2010).
CO and CO-RMs exhibit a wide range of biological effects resulting in specific responses that involve a restricted number of intracellular pathways and targets that encompass inflammation,
Conflict of interest statement
The authors declare that they have no personal, financial or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence, or be perceived to influence, the work submitted.
Acknowledgments
The authors thank Martine Goiset for secretarial assistance and Philip Bastable for English revision of the manuscript.
This work was supported by grants from the French Ministry of Research, from the Regional Council of Burgundy and from the Association de Cardiologie de Bourgogne.
References (223)
- et al.
Oxidases and peroxidases in cardiovascular and lung disease: new concepts in reactive oxygen species signaling
Free Radic Biol Med
(2011) - et al.
Chain scission of hyaluronan by carbonate and dichloride radical anions: potential reactive oxidative species in inflammation?
Free Radic Biol Med
(2006) - et al.
Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway
Hepatology
(2002) - et al.
Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages
Mol Immunol
(2008) - et al.
Nitrogen dioxide and carbonate radical anion: two emerging radicals in biology
Free Radic Biol Med
(2002) - et al.
Effects of exhaustive exercise and vitamin B6 deficiency on free radical oxidative process in male trained rats
Free Radic Biol Med
(1996) - et al.
Inhibition of VCAM-1 expression in endothelial cells by CORM-3: the role of the ubiquitin-proteasome system, p38, and mitochondrial respiration
Free Radic Biol Med
(2012) - et al.
Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes: role for heme oxygenase-1 down-modulation
Chem Biol Interact
(2009) - et al.
Carbon monoxide orchestrates a protective response through PPARgamma
Immunity
(2006) - et al.
Epoxyeicosatrienoic acids and heme oxygenase-1 interaction attenuates diabetes and metabolic syndrome complications
Prostaglandins Other Lipid Mediat
(2012)
Iron trafficking and metabolism in macrophages: contribution to the polarized phenotype
Trends Immunol
High fat diet enhances cardiac abnormalities in SHR rats: protective role of heme oxygenase-adiponectin axis
Diabetol Metab Syndr
Carbon monoxide rescues heme oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation
Am J Pathol
Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1
Hepatology
p38(MAPK): stress responses from molecular mechanisms to therapeutics
Trends Mol Med
Carbon monoxide actuates O(2)-limited heme degradation in the rat brain
Free Radic Biol Med
Stage-dependent activation of cell cycle and apoptosis mechanisms in the right ventricle by pressure overload
Biochim Biophys Acta
Downregulation and nuclear relocation of MLP during the progression of right ventricular hypertrophy induced by chronic pressure overload
J Mol Cell Cardiol
General oxidative stress during doxorubicin-induced cardiotoxicity in rats: absence of cardioprotection and low antioxidant efficiency of alpha-lipoic acid
Biochimie
JunB and JunD regulate human heme oxygenase-1 gene expression in renal epithelial cells
J Biol Chem
Effect of nitric oxide and nitroxide SOD-mimic on the recovery of isolated rat heart following ischemia and reperfusion
Biochem Pharmacol
The protective role of ROS in autoimmune disease
Trends Immunol
Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation
Mol Aspects Med
Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1
Exp Cell Res
Oxidative stress and diabetic cardiovascular complications
Free Radic Biol Med
Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids
Free Radic Biol Med
Antioxidant-induced phosphorylation of tyrosine 486 leads to rapid nuclear export of Bach1 that allows Nrf2 to bind to the antioxidant response element and activate defensive gene expression
J Biol Chem
Glycosaminoglycans are fragmented by hydroxyl, carbonate, and nitrogen dioxide radicals in a site-selective manner: implications for peroxynitrite-mediated damage at sites of inflammation
Free Radic Biol Med
Control of intracellular heme levels: heme transporters and heme oxygenases
Biochim Biophys Acta
Electrophilic nitro-fatty acids: anti-inflammatory mediators in the vascular compartment
Curr Opin Pharmacol
Activation of vascular endothelial nitric oxide synthase and heme oxygenase-1 expression by electrophilic nitro-fatty acids
Free Radic Biol Med
Time course of asymmetric dimethylarginine (ADMA) and oxidative stress in fructose-hypertensive rats: a model related to metabolic syndrome
Atherosclerosis
Asymmetric dimethylarginine (ADMA) and hyperhomocysteinemia in patients with acute myocardial infarction
Clin Biochem
Role of carbon monoxide and nitric oxide in adult rat hepatocytes proliferating in vitro: Effects of CAS 1609
Nitric Oxide
A cholesterol-rich diet improves resistance to ischemic insult in mouse hearts but suppresses the beneficial effect of post-conditioning
J Heart Lung Transplant
Erythropoietin controls heme metabolic enzymes in normal human bone marrow culture
Exp Hematol
Heme oxygenase-1 is upregulated in the kidney of angiotensin II-induced hypertensive rats: possible role in renoprotection
Hypertension
Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury
FASEB J
Carbon monoxide rapidly impairs alveolar fluid clearance by inhibiting epithelial sodium channels
Am J Respir Cell Mol Biol
Regulatory role of dendritic cells in post-infarction healing and left ventricular remodeling
Circulation
Carbon monoxide protects against ischemia–reperfusion injury in an experimental model of controlled nonheartbeating donor kidney
Transplantation
Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment
Antioxid Redox Signal
Role of carbon monoxide in vascular diseases
Curr Pharm Biotechnol
Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress
Antioxid Redox Signal
Bench-to-bedside review: carbon monoxide—from mitochondrial poisoning to therapeutic use
Crit Care
Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury
FASEB J
Role and function of macrophages in the metabolic syndrome
Biochem J
Heme oxygenase and carbon monoxide initiate homeostatic signaling
J Mol Med
Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis
J Exp Med
Haem oxygenase-1 and cardiovascular disease: mechanisms and therapeutic potential
Clin Sci (Lond)
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