Carbon monoxide: Mechanisms of action and potential clinical implications

https://doi.org/10.1016/j.pharmthera.2012.09.007Get rights and content

Abstract

Small amounts of carbon monoxide (CO) are continuously produced in mammals. The intracellular levels of CO can increase under stressful conditions following the induction of HO-1 (heme oxygnase-1), a ubiquitous enzyme responsible for the catabolism of heme. Unlike nitric oxide, which is a free radical, CO does not contain free electrons but may be involved in oxidative stress. The carbonate radical has been proposed to be a key mediator of oxidative damage resulting from peroxynitrite production, likewise, the precursor of the carbonate radical anion being bicarbonate and carbon dioxide. We report herein some of the transcription factors and protein kinases involved in the regulation of vascular HO-1 expression. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against apoptosis and endothelial oxidative damage. Abnormal metabolism and function of CO contribute to the pathogenesis and development of cardiovascular diseases. Important results have been reported in which CO and CO-releasing molecules (CO-RMs) prevent intimal hyperplasia by arresting hyperproliferative vascular smooth muscle cells and increased mobilization and recruitment of bone-marrow-derived progenitor cells. Clinical studies have demonstrated beneficial properties of CO-RMs in transplantation. The anti-inflammatory properties of CO and CO-RMs have been demonstrated in a multitude of animal models of inflammation, suggesting a possible therapeutic application for inflammatory diseases. The development of a technology concerning CO-RMs that controls the delivery and action of CO under different pathological conditions represents a major step forward in the development of CO-based pharmaceuticals with therapeutic applications.

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 (O2radical dot), hydroxyl radical (radical dotOH) and reactive nitrogen species (RNS) such as nitric oxide (radical dotNO) (Halliwell, 2007a). It has brought into focus reactive species described by chemists but forgotten in biology. About 0.3% of O2radical dot present in cell cytosol exists in its protonated form: hydroperoxyl radical (HO2radical dot). Water (H2O) can be split into two free radicals: radical dotOH and hydrogen radical (Hradical dot). The transmembrane electrochemical potential is a major force in cellular energy production. Several free radicals, including thiyl radicals (RSradical dot) and nitrogen dioxide (NO2radical dot) 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: HSradical dot. 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 (CO3radical dot) 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 radical dotOH 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 (CO3radical dot) 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+-radical dotOH) 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.

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