![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOXICOLOGY
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom (P.S., J.H., R.F., R.M.); and Department of Chemistry, University of York, Heslington, York, United Kingdom (I.J.S.F., B.M., C.T.O., J.M.L., A.K.D.-K.)
Received January 23, 2006; accepted April 6, 2006.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
-4-(4-bromo-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [-4-(4-chloro-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [-4-(4-methyl-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F11)] or a hydrogen [-4-(4-chloro-2-pyrone)tricarbonyl iron (0) (CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4-position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.
; Wang, 1998), exerts anti-inflammatory actions (Otterbein et al., 2000), inhibits platelet aggregation (Brune and Ullrich, 1988), and acts as a signaling mediator in both apoptotic and antiapoptotic processes (Song et al., 2004; Zhang et al., 2004). The importance of CO in biology and medicine can be better appreciated by considering the multifunctional activities of heme oxygenase-1 (HO-1), a redox-sensitive-inducible enzyme that generates CO upon degradation of heme during conditions of intense oxidative or nitrosative stress (Motterlini et al., 2002c). Indeed, the induction of HO-1 seems to be central in the adaptation of tissues to a multitude of threatening conditions (Otterbein et al., 2003b). The signaling effects elicited by increased CO production in various experimental models are currently under scrutiny because they may reveal important clues about the cytoprotective nature of the HO-1 pathway. In line with this concept, recent studies have reported that low concentrations of CO gas can be utilized for therapeutic purposes in the resolution of various pathological states (Nakao et al., 2003; Otterbein et al., 2003a,c; Lavitrano et al., 2004). Notably, the identification and characterization of compounds that liberate CO in biological environments could offer a unique opportunity to implement the development of novel strategic approaches based on CO therapy (Motterlini et al., 2003).
Until recently, the use of CO gas administered to cellular and animal experimental models was the only available approach to mimic the physiological role of the HO-1/CO pathway. The discovery that transition metal carbonyls can act effectively as CO-releasing molecules (CO-RMs) in a number of in vitro, ex vivo, and in vivo models demonstrated that the delivery of CO is attainable by storing this gas in a stable chemical form (carbonyl transition metal complex), which could carry and supply CO to tissues in a more controllable fashion than achieved with CO gas (Motterlini et al., 2002b, 2003). The metal complexes, dimanganese decacarbonyl (CORM-1) and tricarbonyldichloro ruthenium(II) dimer (CORM-2), were the first to show promising CO-dependent pharmacological activities such as relaxation of blood vessels, inhibition of coronary vasoconstriction, and mitigation of acute hypertension (Motterlini et al., 2002a). The findings on these two metal carbonyls, which are sparingly soluble in water, prompted the design of additional compounds with similar chemical structures and improved bioactive properties. Tricarbonylchloro(glycinato)ruthenium(II) (CORM-3), the first prototypic water-soluble CO-RM, was subsequently synthesized, and our experiments confirmed that CO, rapidly liberated from this compound, exerts important biological effects including vasodilatation and hypotension (Foresti et al., 2004), cardioprotection against ischemia-reperfusion injury and myocardial infarction (Clark et al., 2003; Guo et al., 2004), prevention of organ graft rejection following heart transplantation (Clark et al., 2003), as well as inhibition of the inflammatory response in macrophages (Sawle et al., 2005). More recently, we have reported on the vasorelaxant and hypotensive properties of sodium boranocarbonate (CORM-A1), a boron-based carbonylating agent that liberates CO in a pH-dependent manner and that under physiological conditions releases CO at a slower rate compared with CORM-3 (Motterlini et al., 2005b; Sandouka et al., 2006). Thus, based on the chemistry of metal carbonyls and decarbonylation reactions in aqueous solutions, we have identified compounds that meet the criteria of biologically active CO carriers and proposed that CO-RMs could be developed as suitable pharmaceutical agents (Motterlini et al., 2003, 2005a). In addition, CO-RMs may be used as an expedient to identify and elucidate new mechanisms mediated by CO (Chatterjee, 2004; Sandouka et al., 2005; Taille et al., 2005), and an increasing number of reports substantiate the feasibility of this new approach (Jozkowicz et al., 2003; Stanford et al., 2003; Arregui et al., 2004; Rattan et al., 2004; Tongers et al., 2004; Xi et al., 2004; Allanson and Reeve, 2005; Desmard et al., 2005).
Thus, the identification of new chemicals that have the propensity to liberate CO may provide important information for optimizing therapies based on the use of CO in its naked form (as a gas). Here, we extend our knowledge on the bioactivity of CO-RMs in tissue and cellular systems by analyzing the profile of CO release, cytotoxicity, vasorelaxation, and anti-inflammatory properties of a class of iron-containing metal carbonyls. A rationale on how the chemical structure of these new compounds can be modified to retain CO-dependent effects and reduce cellular toxicity is presented.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
).
|
Preparation of Solutions and Reagents. Stock solutions of CO-RMs (in DMSO) were prepared freshly on the day of the experiments and used within 1 min from the preparation. Lipopolysaccharide (LPS; Escherichia coli serotype 026:B6) was obtained from Sigma (Poole, Dorset, UK). All other chemicals were reagent grade and obtained from Sigma unless otherwise stated.
Cell Culture. Murine RAW264.7 monocyte macrophages were purchased from the European Collection of Cell Cultures (Salisbury, Wiltshire, UK) and cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin, and 0.1 mg/ml streptomycin. Cultures were maintained at 37°C in a 5% CO2 humidified atmosphere and experiments were conducted on cells at approximately 80 to 90% confluence as described previously (Motterlini et al., 2002a; Sawle et al., 2005). RAW264.7 macrophages were treated with increasing concentrations of CO-RMs (10-200 µM) for 24 h using 24-well plates. At the end of the incubation period, the culture medium was collected for the lactate dehydrogenase (LDH) release assay and the nitrite assay, whereas cells were used for assessing cell metabolism using the Alamar blue assay.
Determination of CO Release Using the Myoglobin Assay. The release of CO from iron-containing CO-RMs was assessed spectrophotometrically by measuring the conversion of deoxymyoglobin (deoxy-Mb) to carbonmonoxy myoglobin (MbCO) as previously reported by our group (Motterlini et al., 2002a, 2003; Clark et al., 2003). A small aliquot of concentrated CO-RM solutions (final concentration of CO-RM: 10, 20, and 40 µM) was added to 1 ml of deoxy-Mb solution (final concentration of Mb: 53 µM) in phosphate buffer, and changes in the Mb spectra were recorded over time. The concentration of MbCO formed was quantified by measuring the absorbance at 540 nm (extinction coefficient = 15.4 M/cm) and plotted over time. The amount of MbCO formed is expressed in the graph as micromolar, and the initial rate was calculated from the fitted curves. Because we used 1 ml of solution containing myoglobin, the rate of MbCO formed (and by inference the amount of CO liberated over time) is reported in the text as nanomoles per minute [moles = volume (liters) x molar].
Cell Viability and Cell Injury Assays. Cell viability was determined in macrophages using an Alamar Blue assay kit and carried out according to the manufacturer's instructions (Serotec, Oxford, UK) as previously reported by us (Clark et al., 2000). The assay is based on the detection of metabolic activity of living cells using a redox indicator that changes from an oxidized (blue) form to a reduced (red) form. The intensity of the red color is proportional to the metabolism of the cells, which is calculated as the difference in absorbance between 570 and 600 nm and expressed as a percentage of control. LDH released in the medium was also measured and used as an index of cellular damage.
|
). This measurement is an indication of NO production following stimulation of inducible nitric-oxide synthase. In brief, the medium from treated cells cultured in 24-well plates was removed and placed into a 96-well plate (50 µl/well). The Griess reagent was added to each well to begin the reaction, the plate was shaken for 10 min, and the absorbance was read at 550 nm on a Molecular Devices VERSAmax plate reader (Molecular Devices, Sunnyvale, CA). The nitrite level in each sample was calculated from a standard curve generated with sodium nitrite (0-300 µM in cell culture medium).
Aortic Ring Preparation. Transverse ring sections were prepared from thoracic aortas of male adult Sprague-Dawley rats (350 g) as described previously (Sammut et al., 1998; Motterlini et al., 2002a; Foresti et al., 2004). After removal of superficial fat and connective tissue, the aorta was cut into rings and mounted in organ baths containing normal Krebs-Henseleit solution with the following composition: 118 mM NaCl, 4.7 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4.7H2O, 22 mM NaHCO3, 11 mM glucose, 0.03 mM K+ EDTA, and 2.5 mM CaCl2. The bath solution was maintained at 37°C and bubbled continuously with a mixture of 95% O2 and 5% CO2. Aortic rings were equilibrated for 60 min at a resting tension of 2g and precontracted with KCl (110 mM) before specific experimental protocols were initiated. Responses were recorded isometrically via a force transducer connected to a Power Lab recording system (ADInstruments Pty Ltd., Castle Hill, Australia). The extent of vasorelaxation over time elicited by a single addition of CO-RMs (100 µM) was assessed in aortic rings precontracted with phenylephrine (1 µM) and compared with the effect produced by the vehicle (DMSO). Vasorelaxation was expressed as a reduction (in percentage) of the initial contraction produced by phenylephrine.
Statistical Analysis. Statistical analysis was performed using analysis of variance combined with Bonferroni test. Differences were considered to be significant at p < 0.05.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Clark et al., 2003). The absorption spectra and the amount of MbCO formed over time after reacting deoxy-Mb with CORM-F3, an iron (0) tricarbonyl-2-pyrone complex, which contains a bromide at 4-position and a methyl group at 6-position of the 2-pyrone ring, are represented in Fig. 2, A and B, respectively. As shown, CORM-F3 gradually liberates CO over time, and the calculated rate of CO release is 0.19 nmol/min. Notably, when the bromide at the 4-position of the 2-pyrone is substituted with a chloride group as in CORM-F8, the rate of CO release is significantly decreased to 0.041 nmol/min (Fig. 3, A and B). A further substantial decrease in the rate of CO release is observed when the methyl group at the 6-position is substituted with a hydrogen as in CORM-F7 (0.007 nmol/min, see Fig. 4, A and B), or the halogen at the 4-position is substituted with another methyl group as in CORM-F11 (no CO release detected, see Fig. 5, A and B). These data clearly indicate the importance of the halogen group at the 4-position of the 2-pyrone ring present in both CORM-F3 and CORM-F8 in modulating the liberation of CO from these iron (0) tricarbonyl complexes.
|
|
|
Cytotoxicity Profile of Iron-Containing CO-RMs. The two compounds showing CO release (CORM-F3 and CORM-F8) were also found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. The percentage of LDH release was measured as an index of cell injury, whereas the Alamar Blue assay was used to determine the degree of cell viability after incubation of CO-RMs for 24 h. As shown in Fig. 2, C and D, cells incubated with increasing concentrations of CORM-F3 showed that this compound did not cause any detectable cytotoxicity when used at concentrations between 10 and 100 µM, whereas 200 µM CORM-F3 caused a 44 ± 3.1% in LDH release and 21 ± 1.5% loss in cell viability. CORM-F8 started to cause some degree of toxic effects already at 100 µM (LDH release = 6.0 ± 1.1%), and at a higher concentration (200 µM), this compound promoted a 27 ± 1.9% in LDH release and 44 ± 3.6% decrease in cell viability (Fig. 3, C and D). Both CORM-F7 and CORM-F11 were more damaging to the cells since at 100 µM they already caused a significant LDH release (Figs. 4C and 5C, respectively), and at 200 µM, they promoted a marked decrease in cell viability (Figs. 4D and 5D, respectively).
Anti-Inflammatory and Vasodilatory Properties of CORM-F3. Because CORM-F3 showed the most promising profile in terms of CO release and cell injury, this compound was investigated further to assess its potential anti-inflammatory and vasodilatory properties. Addition of CORM-F3 (10-100 µM) to RAW264.7 macrophages, stimulated with 1 µg/ml LPS, resulted in a significant and concentration-dependent decrease in nitrite production (Fig. 6A). Moreover, addition of 100 µM CORM-F3 to isolated aortic rings precontracted with phenylephrine elicited a marked and significant vasodilatory effect (30.9 ± 1.3%) compared with control groups treated with vehicle, DMSO (2.2 ± 1.2%, p < 0.05). These data suggest that CO released from CORM-F3 exerts bioactive functions that are typical of CO gas.
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). The results obtained with transition metal carbonyls such as CORM-2 (Motterlini et al., 2002a) and CORM-3 (Clark et al., 2003), as well as the carbonylating agent CORM-A1 (Motterlini et al., 2005b), substantiated the concept that a "solid form" of CO could be used to simulate the pharmacological activities typical of CO gas and HO-1 induction (Motterlini et al., 2005a). From a chemical and pharmacological perspective, the discovery that the rate of CO release from CO-RMs can be finely modulated to achieve a "fast" or "slow" release and consequently allows the modification of the ensuing biological effect (Motterlini et al., 2005a,b) offers a unique opportunity to better understand the mechanism of CO liberation from these compounds. This is particularly true for transition metal carbonyl complexes where the bond of the CO groups can be rendered more or less labile depending on the type of ligand coordinated to the metal center (Motterlini et al., 2003, 2005a); in addition, the different substituents can also affect the degree of toxicity and, therefore, the overall biological activity of the compound.
Here, we present data on a novel class of iron (0) tricarbonyl complexes containing a 2-pyrone motif and demonstrate that they function as CO-RMs in biological systems. There are precedents showing that 2-pyrone derivatives can be used in biological systems. Indeed, substituted 2-pyrones have been reported to inhibit proliferation of ovarian cancer cells in vitro and exhibited no major toxic effects when used at low micromolar concentrations (5-20 µM) in normal cells (Marrison et al., 2002; Fairlamb et al., 2004). In the present study, complexation of the 2-pyrone with an iron (0) tricarbonyl unit serves to activate the ring system, and the nature of the substituents has a profound affect on both the rate and extent of CO release and the associated biological effects. Specifically, CORM-F3, which possesses a bromine substituent at position-4 and a methyl group at position-6 of the 2-pyrone, promotes the liberation of CO at a rate of 0.19 nmol/min. Notably, the substitution of the bromine with a chlorine, as in CORM-F8, renders the compound less prone to release CO as the rate decreases by 4.6-fold. Additional substitutions at the 4- and 6-position with methyl groups (CORM-F11) further decrease the ability of the compound to liberate CO. Of significant interest is that the types of substituent(s) on the 2-pyrone ring not only influence the kinetics of CO release but also the extent of cytotoxicity inflicted to cells in culture. In fact, among the CO-RMs tested, CORM-F3 was the iron (0) tricarbonyl complex that caused less cell injury and, at the concentration of 100 µM, did not affect cell viability in RAW246.7 macrophages. Conceptually, these data are in line with previously reported results on ruthenium-based CO-RMs where replacement of a Ru(CO)3Cl motif from CORM-2 with a glycine to obtain CORM-3 resulted in marked reduction of the cytotoxic effects caused to smooth muscle cells in culture (Motterlini et al., 2002a, 2005a). The demonstration that iron-containing carbonyls function as CO-RMs is of some consequence since iron is a naturally occurring metal present in abundance in both structural and functional proteins and can be easily removed and transported in the blood (e.g., by transferrin), whereas only traces of ruthenium can be found in biological systems (Finney and O'Halloran, 2003). Nevertheless, it is also important to emphasize that the perception that transition metals are inherently toxic to mammals is inaccurate and needs to be revisited (Clarke, 2002) because substitution or coordination to appropriate biological ligands, as shown here and in previous reports (Clark et al., 2003; Motterlini et al., 2005a), can dramatically change the bioactive properties of the metal center and shield from or eliminate the intrinsic toxicological features of these specific compounds. In fact, ruthenium-based compounds are currently being developed as anticancer agents, and other transition metals such as vanadium and gold have been used as central parts of molecules that have therapeutic properties in a variety of diseases (Clarke, 2002). This is an important aspect for the development of safe pharmaceuticals, and it is envisaged that more effort from both synthetic organometallic and medicinal chemists will substantially improve the pharmacological profile of iron and other transition metal carbonyl complexes (Motterlini et al., 2005a).
Thus, the presence of a bromine group at 4-position of the 2-pyrone ring in CORM-F3 gives rise to a relevant release of CO and a better cytotoxic outcome compared with the other CORM-F compounds. Consequently, this compound was tested further, and it was found that at micromolar concentrations (10-100 µM) to exert both vasodilatory and anti-inflammatory properties in ex vivo and in vitro systems, respectively. These findings are in agreement with previously published results from Motterlini and colleagues showing that a ruthenium-containing carbonyl (CORM-3) elicits profound vasorelaxation in isolated aortic rings (Foresti et al., 2004) and significantly reduces endotoxin-mediated nitrite production in activated macrophages (Sawle et al., 2005). The identification of CORM-F3 as a bioactive iron-containing carbonyl complex broadens the portfolio of molecules that are capable of exerting a physiological effect through the action of CO since a wide range of CO carriers containing manganese (dimanganese decacarbonyl), ruthenium (CORM-2 and CORM-3), and boron (CORM-A1) have been already investigated for their pharmacological properties to alleviate pathological conditions characterized by oxidative stress, acute hypertension, ischemic events, and inflammatory states (Motterlini et al., 2002a, 2005a; Clark et al., 2003; Foresti et al., 2004; Sawle et al., 2005; Sandouka et al., 2006). Future work in the development of novel transition metal carbonyl complexes containing appropriate organic ligand architecture will implement the design of selective CO-RMs that can be adapted for the specific treatment of a certain disease state.
|
Footnotes |
|---|
ABBREVIATIONS: CO, carbon monoxide; HO-1, heme oxygenase-1; CO-RM, carbon monoxide-releasing molecule, iron carbonyl; CORM-1, dimanganese decacarbonyl; CORM-2, tricarbonyldichloro ruthenium(II) dimer; CORM-3, tricarbonylchloro(glycinato)ruthenium(II); CORM-A1, sodium boranocarbonate; DMSO, dimethyl sulfoxide; CORM-F3, -4-(4-bromo-6-methyl-2-pyrone)tricarbonyl iron (0); CORM-F7, -4-(4-chloro-2-pyrone)tricarbonyl iron (0); CORM-F11, -4-(4-methyl-6-methyl-2-pyrone)tricarbonyl iron (0); CORM-F8, -4-(4-chloro-6-methyl-2-pyrone)tricarbonyl iron (0); LPS, lipopolysaccharide; LDH, lactate dehydrogenase; deoxy-Mb, deoxymyoglobin; MbCO, carbonmonoxy myoglobin.
Address correspondence to: Roberto Motterlini, Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK. E-mail: r.motterlini{at}imperial.ac.uk
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Allanson M and Reeve VE (2005) Ultraviolet A (320-400 nm) Modulation of ultraviolet B (290-320 nm)-induced immune suppression is mediated by carbon monoxide. J Investig Dermatol 124: 644-650.[Medline]
Arregui B, Lopez B, Salom MG, Valero F, Navarro C, and Fenoy FJ (2004) Acute renal hemodynamic effects of dimanganese decacarbonyl and cobalt protoporphyrin. Kidney Int 65: 564-574.[CrossRef][Medline]
Brune B and Ullrich V (1988) Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol 32: 497-504.
Chatterjee PK (2004) Water-soluble carbon monoxide-releasing molecules: helping to elucidate the vascular activity of the "silent killer." Br J Pharmacol 142: 391-393.[CrossRef][Medline]
Clark JE, Foresti R, Green CJ, and Motterlini R (2000) Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J 348: 615-619.[CrossRef][Medline]
Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, and Motterlini R (2003) Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 93: e2-e8.
Clarke MJ (2002) Ruthenium metallopharmaceuticals. Coordin Chem Rev 232: 69-93.[CrossRef]
Desmard M, Amara M, Lanone S, Motterlini R, and Boczkowski J (2005) Carbon monoxide reduces the expression and activity of matrix metalloproteinases 1 and 2 in alveolar epithelial cells. Cell Mol Biol 51: 403-408.[Medline]
Fairlamb IJ, Marrison LR, Dickinson JM, Lu FJ, and Schmidt JP (2004) 2-Pyrones possessing antimicrobial and cytotoxic activities. Bioorg Med Chem 12: 4285-4299.[Medline]
Fairlamb IJS, Syvanne SM, and Whitwood AC (2003) Synthesis of (bromo-eta(4)-2-pyrone)tricarbonyliron complexes. Synlett 1693-1697.
Finney LA and O'Halloran TV (2003) Transition metal speciation in the cell: insights from the chemistry of metal ion receptors. Science (Wash DC) 300: 931-936.
Foresti R, Hammad J, Clark JE, Johnson RA, Mann BE, Friebe A, Green CJ, and Motterlini R (2004) Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br J Pharmacol 142: 453-460.[CrossRef][Medline]
Guo Y, Stein AB, Wu WJ, Tan W, Zhu X, Li QH, Dawn B, Motterlini R, and Bolli R (2004) Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am J Physiol 286: H1649-H1653.
Jozkowicz A, Huk I, Nigisch A, Weigel G, Dietrich W, Motterlini R, and Dulak J (2003) Heme oxygenase-1 and angiogenic activity of endothelial cells: stimulation by carbon monoxide, inhibition by tin protoporphyrin IX. Antioxid Redox Signal 5: 155-162.[CrossRef][Medline]
Lavitrano M, Smolenski RT, Musumeci A, Maccherini M, Slominska E, Di Florio E, Bracco A, Mancini A, Stassi G, Patti M, et al. (2004) Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs. FASEB J 18: 1093-1095.
Marrison LR, Dickinson JM, and Fairlamb IJ (2002) Bioactive 4-substituted-6-methyl-2-pyrones with promising cytotoxicity against A2780 and K562 cell lines. Bioorg Med Chem Lett 12: 3509-3513.[Medline]
Motterlini R, Clark JE, Foresti R, Sarathchandra P, Mann BE, and Green CJ (2002a) Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ Res 90: E17-E24.[CrossRef][Medline]
Motterlini R, Foresti R, and Green CJ (2002b) Studies on the development of carbon monoxide-releasing molecules: potential applications for the treatment of cardiovascular dysfunction, in Carbon Monoxide and Cardiovascular Functions (Wang R ed) pp 249-271, CRC Press, Inc., Boca Raton, FL.
Motterlini R, Gonzales A, Foresti R, Clark JE, Green CJ, and Winslow RM (1998) Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ Res 83: 568-577.
Motterlini R, Green CJ, and Foresti R (2002c) Regulation of heme oxygenase-1 by redox signals involving nitric oxide. Antiox Redox Signal 4: 615-624.[CrossRef][Medline]
Motterlini R, Mann BE, and Foresti R (2005a) Therapeutic applications of carbon monoxide-releasing molecules (CO-RMs). Expert Opin Investig Drugs 14: 1305-1318.[CrossRef][Medline]
Motterlini R, Mann BE, Johnson TR, Clark JE, Foresti R, and Green CJ (2003) Bioactivity and pharmacological actions of carbon monoxide-releasing molecules. Curr Pharmacol Design 9: 2525-2539.[CrossRef][Medline]
Motterlini R, Sawle P, Bains S, Hammad J, Alberto R, Foresti R, and Green CJ (2005b) CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule. FASEB J 19: 284-286.
Nakao A, Kimizuka K, Stolz DB, Neto JS, Kaizu T, Choi AM, Uchiyama T, Zuckerbraun BS, Nalesnik MA, Otterbein LE, et al. (2003) Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol 163: 1587-1598.
Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, and Choi AM (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6: 422-428.[CrossRef][Medline]
Otterbein LE, Otterbein SL, Ifedigbo E, Liu F, Morse DE, Fearns C, Ulevitch RJ, Knickelbein R, Flavell RA, and Choi AM (2003a) MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Am J Pathol 163: 2555-2563.
Otterbein LE, Soares MP, Yamashita K, and Bach FH (2003b) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24: 449-455.[CrossRef][Medline]
Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, Csizmadia E, et al. (2003c) Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med 9: 183-190.[CrossRef][Medline]
Rattan S, Haj RA, and De Godoy MA (2004) Mechanism of internal anal sphincter relaxation by CORM-1, authentic CO and NANC nerve stimulation. Am J Physiol 287: G605-G611.
Sammut IA, Foresti R, Clark JE, Exon DJ, Vesely MJJ, Sarathchandra P, Green CJ, and Motterlini R (1998) Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1. Br J Pharmacol 125: 1437-1444.[CrossRef][Medline]
Sandouka A, Balogun E, Foresti R, Mann BE, Johnson TR, Tayem Y, Green CJ, Fuller B, and Motterlini R (2005) Carbon monoxide-releasing molecules (CO-RMs) modulate respiration in isolated mitochondria. Cell Mol Biol 51: 425-432.[Medline]
Sandouka A, Fuller BJ, Mann BE, Green CJ, Foresti R, and Motterlini R (2006) Treatment with carbon monoxide-releasing molecules (CO-RMs) during cold storage improves renal function at reperfusion. Kidney Int 69: 239-247.[CrossRef][Medline]
Sawle P, Foresti R, Mann BE, Johnson TR, Green CJ, and Motterlini R (2005) Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br J Pharmacol 145: 800-810.[CrossRef][Medline]
Song R, Zhou Z, Kim PK, Shapiro RA, Liu F, Ferran C, Choi AM, and Otterbein LE (2004) Carbon monoxide promotes Fas/CD95-induced apoptosis in Jurkat cells. J Biol Chem 279: 44327-44334.
Stanford SJ, Walters MJ, Hislop AA, Haworth SG, Evans TW, Mann BE, Motterlini R, and Mitchell JA (2003) Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role. Eur J Pharmacol 473: 135-141.[CrossRef][Medline]
Taille C, El-Benna J, Lanone S, Boczkowski J, and Motterlini R (2005) Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J Biol Chem 280: 25350-25360.
Tongers J, Fiedler B, Konig D, Kempf T, Klein G, Heineke J, Kraft T, Gambaryan S, Lohmann SM, Drexler H, et al. (2004) Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling and hypertrophy in cardiac myocytes. Cardiovasc Res 63: 545-552.
Wang R (1998) Resurgence of carbon monoxide: an endogenous gaseous vasorelaxing factor. Can J Physiol Pharmacol 76: 1-15.[CrossRef][Medline]
Xi Q, Tcheranova D, Parfenova H, Horowitz B, Leffler CW, and Jaggar JH (2004) Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing apparent Ca2+ sensitivity of 
-subunits. Am J Physiol 286: H610-H618.
Zhang X, Shan P, Alam J, Fu XY, and Lee PJ (2004) Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a PI3K/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem 280: 8714-8721.[Medline]
This article has been cited by other articles:
|
|
 |
|
  E. Masini, A. Vannacci, P. Failli, R. Mastroianni, L. Giannini, M. C. Vinci, C. Uliva, R. Motterlini, and P. F. Mannaioni A carbon monoxide-releasing molecule (CORM-3) abrogates polymorphonuclear granulocyte-induced activation of endothelial cells and mast cells FASEB J, September 1, 2008; 22(9): 3380 - 3388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zimmermann, C. W. Leffler, D. Tcheranova, A. L. Fedinec, and H. Parfenova Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2501 - H2507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Fredenburgh, M. A. Perrella, and S. A. Mitsialis The Role of Heme Oxygenase-1 in Pulmonary Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 158 - 165. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
, p < 0.05 versus LPS alone (gray bar). B, isolated aortic rings were precontracted with phenylephrine (1 µM), and CORM-F3 (100 µM) was then added as reported under Materials and Methods. The percentage of relaxation mediated by CORM-F3 was compared with the ones elicited by the vehicle (DMSO), which was used as a control group. Data represent the mean ± S.E.M. of five independent experiments. *, p < 0.05 versus control (CON).