REVIEW EDITORIAL For reprint orders, please contact: [email protected]
Endogenous carbon monoxide and cardiometabolic risk: can measuring exhaled carbon monoxide be used to refine cardiometabolic risk assessment? “A HO-1-knockout model exhibited dramatic arterial thromboses, which were successfully prevented by administration of exogenous CO, thereby demonstrating that endogenous CO plays a regulatory role in the thrombotic cascade.”
Matthew Nayor*,1,2 & Ramachandran S Vasan1,3,4 Physiology & pathophysiology of endogenous carbon monoxide Best known for its roles as a ‘silent killer’ and environmental pollutant, the gasotransmitter carbon monoxide (CO) is increasingly recognized to be an essential regulator of numerous biological processes. CO is produced endogenously by the enzyme heme oxygenase (HO), which degrades heme to produce CO and biliverdin [1] . HO exists in two forms: HO-2 is constitutively expressed primarily in the brain and testes, while HO-1 is induced by physiologic stress and has been found in almost every cell type [2] . Both HO and CO are essential for healthy development as evidenced by the near-complete lethality of a HO-1-knockout model [3] , as well as by the phenotype of severe growth retardation, systemic iron deposition and endothelial dysfunction reported
in a 6-year-old boy diagnosed with HO-1 deficiency [4] . At physiologic levels, endogenous CO favorably modulates vascular function, thrombosis–hemostasis, apoptosis and adiposity. CO promotes healing from vascular injury by recruiting bone marrow-derived progenitor cells to facilitate re-endothelialization, as well as by preventing pathologic intimal hyperplasia [5,6] . A HO-1-knockout model exhibited dramatic arterial thromboses, which were successfully prevented by administration of exogenous CO, thereby demonstrating that endogenous CO plays a regulatory role in the thrombotic cascade [7] . CO also acts through both the intrinsic and extrinsic pathways to prevent endothelial cell apoptosis [8] . In addition, in a murine model of the metabolic syndrome, chronic low-dose treatment with exogenous CO resulted in
KEYWORDS
• carbon monoxide • cardiometabolic risk • prevention
Framingham Heart Study, Framingham, MA, USA Brigham & Women’s Hospital, Division of Cardiovascular Medicine, 75 Francis Street, Boston, MA 02115, USA 3 Sections of Preventive Medicine & Cardiology, Boston University School of Medicine, Boston, MA, USA 4 Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA *Author for correspondence: [email protected] 1 2
10.2217/FCA.14.78 © 2015 Future Medicine Ltd
Future Cardiol. (2015) 11(1), 9–12
part of
ISSN 1479-6678
9
Editorial Nayor & Vasan
“...consistent with small
animal experimental models, exhaled CO concentrations have been found to be elevated in people with diabetes mellitus, in whom it correlates positively with blood glucose levels.”
10
reductions in blood glucose and insulin levels and attenuated the development of obesity in the mice [9] . Favorable remodeling of adipocytes was hypothesized to be the underlying mechanism responsible for these improvements in metabolic variables. In contrast to the aforementioned experiments supporting the protective effects of endogenous CO at low physiologic concentrations, there are equally persuasive findings implicating elevated concentrations of CO in promoting maladaptive responses. The interaction between CO and the other diatomic gasotransmitter, nitric oxide (NO), serves as a clear example of this possibility. At low levels, CO is synergistic with NO, promoting vasorelaxation via the cyclic guanosine monophosphate pathway and by stimulating NO release [10] . However, at high levels, CO inhibits the production of NO, thereby contributing to vasoconstriction [10] . Although its presence is vital to endothelial integrity, endogenous CO production has been shown to be increased in rats with the metabolic syndrome and associated microvascular dysfunction [11] . By reducing circulating CO via a HO inhibitor, the investigators demonstrated improvements in endothelial function [11] . Elevated CO concentrations have also been reported to promote hyperglycemia by stimulating glucagon release [12] , to contribute to mitochondrial oxidative stress [13] and to serve as a local mediator of the hypertensive response to physiologic stress [14] . Thus, endogenous CO has complex effects, with paradoxical actions at high versus low concentrations. Given the accumulation of evidence supporting the important biological effects of CO in both health and disease, interest in understanding the potential clinical implications of CO continues to grow. Human studies In order to investigate how CO functions in human disease states, accurate measurements of circulating CO must be established. Although gas chromatography remains the reference standard, commercially available electrochemical sensors have recently been developed to quantify exhaled CO (eCO) and have been shown to be reproducible and accurate [15] . These technologies leverage the property that CO is eliminated almost exclusively by the lungs, and therefore concentrations of CO in exhaled samples closely approximate those in the serum, thereby reflecting endogenous CO levels.
Future Cardiol. (2015) 11(1)
Measured with these sensors, elevated eCO has been reported in numerous human disease states. Concentrations of eCO are elevated in the setting of airway inflammation and have been associated with asthma severity [16] . In fact, endogenous CO production can be increased by any disturbance in red blood cell hemostasis [2] , which likely explains the finding of increased eCO levels in critically ill patients [17] . Furthermore, consistent with small animal experimental models, eCO concentrations have been found to be elevated in people with diabetes mellitus, in whom it correlates positively with blood glucose levels [18] . Investigators explored the relationship between eCO concentration and cardiovascular disease in the large community-based Framingham Heart Study (FHS). Cheng and colleagues first related eCO concentrations to the incidence of the metabolic syndrome and clinical cardiovascular disease in 4139 middleaged FHS participants [15] . They reported that higher levels of eCO were associated with an increased risk of both prevalent and incident metabolic syndrome regardless of smoking status. Compared with individuals in the lowest quartile of eCO, those in the highest quartile had a 48% increased risk of developing the metabolic syndrome (p < 0.0001) during the 4-year follow-up period. The investigators also observed eCO to be independently associated with incident cardiovascular disease, with a 65% higher risk in participants in the highest quartile of eCO compared with those in the lowest quartile (p = 0.027). Framingham investigators also evaluated the associations between eCO, subclinical cardiovascular disease and incident cardiovascular disease in a follow-up investigation [19] . The investigators demonstrated a robust association of eCO with prevalent subclinical cardiovascular disease that persisted after adjusting for traditional cardiovascular risk factors and smoking status. The age- and sex-adjusted incidence of cardiovascular disease also increased linearly with eCO concentration. The investigators described several other interesting findings. Participants with both higher eCO levels and subclinical disease developed clinical cardiovascular disease at a rate that was four-times that of those with lower eCO and absence of subclinical disease. In addition, subclinical cardiovascular disease was associated with a higher risk of incident cardiovascular disease in subjects with higher eCO, but not in those with lower eCO. Taken together, these findings
future science group
Endogenous carbon monoxide & cardiometabolic risk suggest that not only is eCO elevated in subjects with subclinical and clinical cardiovascular disease, but elevated eCO is a biomarker of the risk for progression to clinical cardiovascular disease. Future perspective The findings linking elevated eCO with cardiometabolic disease detailed above are provocative and appear to be consistent with experimental studies demonstrating paradoxical, concentration-dependent effects of endogenous CO in numerous disease states. However, before eCO measurements can be considered as a valid marker of cardiometabolic risk, several key issues need to be addressed, including a number of limitations of the previous studies. In these prior reports, eCO was used to quantify endogenous CO. However, eCO is affected not only by endogenous CO production, but also by inhaled CO from smoke and ambient air pollution. Although self-reported smoking status was used to control for smoke inhalation in prior studies, such adjustment may not adequately account for exogenous exposures. Participants may not reliably report their personal smoking history or second-hand smoke exposure. Furthermore, there may be considerable interindividual variability in CO absorption from smoke inhalation. Environmental CO exposure is another important consideration that has not been accounted for in previous analyses. Increased exposure to air pollution is an independent risk factor for cardiovascular disease and CO is a significant component in ambient air [20] . Therefore, controlling for exposure to the CO that is present in air pollution utilizing geographic distance from major roadways, environmental sensors or other innovative methods would be an important addition to future population-based studies of eCO. Indeed, eCO as measured conventionally may reflect a composite of exposure to exogenous CO and endogenous concentrations of this gasotransmitter. These limitations of previous investigations identify several important avenues for future research. The relationships between eCO concentrations and other cardiovascular-related outcomes, such as chronic kidney disease and heart failure, have yet to be evaluated and may provide additional information regarding the incremental prognostic yield from eCO in terms of understanding and estimating cardiovascular risk in a broader context. Furthermore, additional bioactive molecules/biomarkers can be measured in
future science group
breath condensates; investigating their respective functions and interactions with CO may shed further light on their combined influence on cardiometabolic risk. These include the other gasotransmitters – hydrogen sulfide and NO – which are known to play important roles in vascular regulation, as well as nonvolatile substances, such as cytokines and certain peptides that have not yet been evaluated in this context [1] . Finally, investigations are necessary to elucidate the mechanisms underlying the reported associations between CO and cardiometabolic outcomes. Extrapolating from preclinical studies, there are at least two biologically plausible explanations for this. First, endogenous CO production may be increased as a compensatory response to the physiologic stress imposed by the metabolic syndrome and subclinical cardiovascular disease. If this explanation is confirmed, eCO may prove to be an informative, cheap and noninvasive biomarker of cardiometabolic risk. The second potential explanation is that increased eCO levels are in fact pathogenic and lead to clinical cardiovascular disease. In this case, CO may prove to be a valuable drug target. Despite the gaps in our current knowledge, there is considerable evidence supporting an important and potentially causal role for CO in c ardiometabolic disease. In summary, CO has complex relationships with physiological processes, presumably as a function of low versus high concentrations (Supplementary Figure 1; see online at www.futuremedicine.com/doi/full/10.2217/FCA.14.78). These data raise the possibility of a narrow range of CO that is conducive to better health, with opposite effects being observed when a putative threshold is crossed. Further studies are needed to elucidate whether CO concentrations can be used clinically as a biomarker of cardiometabolic risk or a target of drug therapy.
Editorial
“The relationships between exhaled CO concentrations and other cardiovascular-related outcomes, such as chronic kidney disease and heart failure, have yet to be evaluated...”
Financial & competing interests disclosure This work was supported by NIH grant T32-HL007604 (M Nayor) and by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contract N01-HC-25195). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
11
Editorial Nayor & Vasan endothelial cell apoptosis by inhibiting reactive oxygen species formation. J. Biol. Chem. 282(3), 1718–1726 (2007).
References Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
Szabo C. Gaseotransmitters: new frontiers for translational science. Sci. Transl. Med. 2(59), 59ps54 (2010).
2
Owens EO. Endogenous carbon monoxide production in disease. Clin. Biochem. 43(15), 1183–1188 (2010).
•• Excellent review of the function of carbon monoxide in several disease states. 3
4
Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl Acad. Sci. USA 94(20), 10925–10930 (1997). Yachie A, Niida Y, Wada T et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 103(1), 129–135 (1999).
5
Wegiel B, Gallo DJ, Raman KG et al. Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation 121(4), 537–548 (2010).
6
Otterbein LE, Zuckerbraun BS, Haga M et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat. Med. 9(2), 183–190 (2003).
7
•
8
12
True AL, Olive M, Boehm M et al. Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide. Circ. Res. 101(9), 893–901 (2007). Description of the protective role of carbon monoxide on endothelial function and thrombosis. Wang X, Wang Y, Kim HP, Nakahira K, Ryter SW, Choi AM. Carbon monoxide protects against hyperoxia-induced
9
Hosick PA, Alamodi AA, Storm MV et al. Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. Int. J. Obes. (Lond.) 38(1), 132–139 (2014).
10 Thorup C, Jones CL, Gross SS, Moore LC,
Goligorsky MS. Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS. Am. J. Physiol. 277(6 Pt 2), F882–F889 (1999). •
Investigation of the concentrationdependent relationship between carbon monoxide and nitric oxide.
11 Johnson FK, Johnson RA, Durante W,
Jackson KE, Stevenson BK, Peyton KJ. Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290(3), R601–R608 (2006). 12 Henningsson R, Alm P, Ekström P,
Lundquist I. Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. Diabetes 48(1), 66–76 (1999). 13 Thom SR, Xu YA, Ischiropoulos H. Vascular
endothelial cells generate peroxynitrite in response to carbon monoxide exposure. Chem. Res. Toxicol. 10(9), 1023–1031 (1997). 14 Motterlini R, Gonzales A, Foresti R, Clark
JE, Green CJ, Winslow RM. Heme oxygenase-1 derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ. Res. 83(5), 568–577 (1998).
Future Cardiol. (2015) 11(1)
15 Cheng S, Lyass A, Massaro JM, O’connor
GT, Keaney JF Jr, Vasan RS. Exhaled carbon monoxide and risk of metabolic syndrome and cardiovascular disease in the community. Circulation 122(15), 1470–1477 (2010). •• Population-based study of the relationships between exhaled carbon monoxide levels, the metabolic syndrome and incident cardiovascular disease. 16 Zhang J, Yao X, Yu R et al. Exhaled carbon
monoxide in asthmatics: a meta-analysis. Respir. Res. 11, 50 (2010). 17 Scharte M, Bone HG, Van Aken H, Meyer
J. Increased carbon monoxide in exhaled air of critically ill patients. Biochem. Biophys. Res. Commun. 267(1), 423–426 (2000). 18 Paredi P, Biernacki W, Invernizzi G,
Kharitonov SA, Barnes PJ. Exhaled carbon monoxide levels elevated in diabetes and correlated with glucose concentration in blood: a new test for monitoring the disease? Chest 116(4), 1007–1011 (1999). 19 Cheng S, Enserro D, Xanthakis V et al.
Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes. Eur. Heart J. 35(42), 2980–2987 (2014). •• Investigation of the associations between exhaled carbon monoxide, subclinical cardiovascular disease and clinical cardiovascular events in a community-based cohort. 20 Puett RC, Schwartz J, Hart JE et al.
Chronic particulate exposure, mortality, and coronary heart disease in the Nurses’ Health Study. Am. J. Epidemiol. 168(10), 1161–1168 (2008).
future science group
Endogenous carbon monoxide and cardiometabolic risk: can measuring exhaled carbon monoxide be used to refine cardiometabolic risk assessment? “A HO-1-knockout model exhibited dramatic arterial thromboses, which were successfully prevented by administration of exogenous CO, thereby demonstrating that endogenous CO plays a regulatory role in the thrombotic cascade.”
Matthew Nayor*,1,2 & Ramachandran S Vasan1,3,4 Physiology & pathophysiology of endogenous carbon monoxide Best known for its roles as a ‘silent killer’ and environmental pollutant, the gasotransmitter carbon monoxide (CO) is increasingly recognized to be an essential regulator of numerous biological processes. CO is produced endogenously by the enzyme heme oxygenase (HO), which degrades heme to produce CO and biliverdin [1] . HO exists in two forms: HO-2 is constitutively expressed primarily in the brain and testes, while HO-1 is induced by physiologic stress and has been found in almost every cell type [2] . Both HO and CO are essential for healthy development as evidenced by the near-complete lethality of a HO-1-knockout model [3] , as well as by the phenotype of severe growth retardation, systemic iron deposition and endothelial dysfunction reported
in a 6-year-old boy diagnosed with HO-1 deficiency [4] . At physiologic levels, endogenous CO favorably modulates vascular function, thrombosis–hemostasis, apoptosis and adiposity. CO promotes healing from vascular injury by recruiting bone marrow-derived progenitor cells to facilitate re-endothelialization, as well as by preventing pathologic intimal hyperplasia [5,6] . A HO-1-knockout model exhibited dramatic arterial thromboses, which were successfully prevented by administration of exogenous CO, thereby demonstrating that endogenous CO plays a regulatory role in the thrombotic cascade [7] . CO also acts through both the intrinsic and extrinsic pathways to prevent endothelial cell apoptosis [8] . In addition, in a murine model of the metabolic syndrome, chronic low-dose treatment with exogenous CO resulted in
KEYWORDS
• carbon monoxide • cardiometabolic risk • prevention
Framingham Heart Study, Framingham, MA, USA Brigham & Women’s Hospital, Division of Cardiovascular Medicine, 75 Francis Street, Boston, MA 02115, USA 3 Sections of Preventive Medicine & Cardiology, Boston University School of Medicine, Boston, MA, USA 4 Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA *Author for correspondence: [email protected] 1 2
10.2217/FCA.14.78 © 2015 Future Medicine Ltd
Future Cardiol. (2015) 11(1), 9–12
part of
ISSN 1479-6678
9
Editorial Nayor & Vasan
“...consistent with small
animal experimental models, exhaled CO concentrations have been found to be elevated in people with diabetes mellitus, in whom it correlates positively with blood glucose levels.”
10
reductions in blood glucose and insulin levels and attenuated the development of obesity in the mice [9] . Favorable remodeling of adipocytes was hypothesized to be the underlying mechanism responsible for these improvements in metabolic variables. In contrast to the aforementioned experiments supporting the protective effects of endogenous CO at low physiologic concentrations, there are equally persuasive findings implicating elevated concentrations of CO in promoting maladaptive responses. The interaction between CO and the other diatomic gasotransmitter, nitric oxide (NO), serves as a clear example of this possibility. At low levels, CO is synergistic with NO, promoting vasorelaxation via the cyclic guanosine monophosphate pathway and by stimulating NO release [10] . However, at high levels, CO inhibits the production of NO, thereby contributing to vasoconstriction [10] . Although its presence is vital to endothelial integrity, endogenous CO production has been shown to be increased in rats with the metabolic syndrome and associated microvascular dysfunction [11] . By reducing circulating CO via a HO inhibitor, the investigators demonstrated improvements in endothelial function [11] . Elevated CO concentrations have also been reported to promote hyperglycemia by stimulating glucagon release [12] , to contribute to mitochondrial oxidative stress [13] and to serve as a local mediator of the hypertensive response to physiologic stress [14] . Thus, endogenous CO has complex effects, with paradoxical actions at high versus low concentrations. Given the accumulation of evidence supporting the important biological effects of CO in both health and disease, interest in understanding the potential clinical implications of CO continues to grow. Human studies In order to investigate how CO functions in human disease states, accurate measurements of circulating CO must be established. Although gas chromatography remains the reference standard, commercially available electrochemical sensors have recently been developed to quantify exhaled CO (eCO) and have been shown to be reproducible and accurate [15] . These technologies leverage the property that CO is eliminated almost exclusively by the lungs, and therefore concentrations of CO in exhaled samples closely approximate those in the serum, thereby reflecting endogenous CO levels.
Future Cardiol. (2015) 11(1)
Measured with these sensors, elevated eCO has been reported in numerous human disease states. Concentrations of eCO are elevated in the setting of airway inflammation and have been associated with asthma severity [16] . In fact, endogenous CO production can be increased by any disturbance in red blood cell hemostasis [2] , which likely explains the finding of increased eCO levels in critically ill patients [17] . Furthermore, consistent with small animal experimental models, eCO concentrations have been found to be elevated in people with diabetes mellitus, in whom it correlates positively with blood glucose levels [18] . Investigators explored the relationship between eCO concentration and cardiovascular disease in the large community-based Framingham Heart Study (FHS). Cheng and colleagues first related eCO concentrations to the incidence of the metabolic syndrome and clinical cardiovascular disease in 4139 middleaged FHS participants [15] . They reported that higher levels of eCO were associated with an increased risk of both prevalent and incident metabolic syndrome regardless of smoking status. Compared with individuals in the lowest quartile of eCO, those in the highest quartile had a 48% increased risk of developing the metabolic syndrome (p < 0.0001) during the 4-year follow-up period. The investigators also observed eCO to be independently associated with incident cardiovascular disease, with a 65% higher risk in participants in the highest quartile of eCO compared with those in the lowest quartile (p = 0.027). Framingham investigators also evaluated the associations between eCO, subclinical cardiovascular disease and incident cardiovascular disease in a follow-up investigation [19] . The investigators demonstrated a robust association of eCO with prevalent subclinical cardiovascular disease that persisted after adjusting for traditional cardiovascular risk factors and smoking status. The age- and sex-adjusted incidence of cardiovascular disease also increased linearly with eCO concentration. The investigators described several other interesting findings. Participants with both higher eCO levels and subclinical disease developed clinical cardiovascular disease at a rate that was four-times that of those with lower eCO and absence of subclinical disease. In addition, subclinical cardiovascular disease was associated with a higher risk of incident cardiovascular disease in subjects with higher eCO, but not in those with lower eCO. Taken together, these findings
future science group
Endogenous carbon monoxide & cardiometabolic risk suggest that not only is eCO elevated in subjects with subclinical and clinical cardiovascular disease, but elevated eCO is a biomarker of the risk for progression to clinical cardiovascular disease. Future perspective The findings linking elevated eCO with cardiometabolic disease detailed above are provocative and appear to be consistent with experimental studies demonstrating paradoxical, concentration-dependent effects of endogenous CO in numerous disease states. However, before eCO measurements can be considered as a valid marker of cardiometabolic risk, several key issues need to be addressed, including a number of limitations of the previous studies. In these prior reports, eCO was used to quantify endogenous CO. However, eCO is affected not only by endogenous CO production, but also by inhaled CO from smoke and ambient air pollution. Although self-reported smoking status was used to control for smoke inhalation in prior studies, such adjustment may not adequately account for exogenous exposures. Participants may not reliably report their personal smoking history or second-hand smoke exposure. Furthermore, there may be considerable interindividual variability in CO absorption from smoke inhalation. Environmental CO exposure is another important consideration that has not been accounted for in previous analyses. Increased exposure to air pollution is an independent risk factor for cardiovascular disease and CO is a significant component in ambient air [20] . Therefore, controlling for exposure to the CO that is present in air pollution utilizing geographic distance from major roadways, environmental sensors or other innovative methods would be an important addition to future population-based studies of eCO. Indeed, eCO as measured conventionally may reflect a composite of exposure to exogenous CO and endogenous concentrations of this gasotransmitter. These limitations of previous investigations identify several important avenues for future research. The relationships between eCO concentrations and other cardiovascular-related outcomes, such as chronic kidney disease and heart failure, have yet to be evaluated and may provide additional information regarding the incremental prognostic yield from eCO in terms of understanding and estimating cardiovascular risk in a broader context. Furthermore, additional bioactive molecules/biomarkers can be measured in
future science group
breath condensates; investigating their respective functions and interactions with CO may shed further light on their combined influence on cardiometabolic risk. These include the other gasotransmitters – hydrogen sulfide and NO – which are known to play important roles in vascular regulation, as well as nonvolatile substances, such as cytokines and certain peptides that have not yet been evaluated in this context [1] . Finally, investigations are necessary to elucidate the mechanisms underlying the reported associations between CO and cardiometabolic outcomes. Extrapolating from preclinical studies, there are at least two biologically plausible explanations for this. First, endogenous CO production may be increased as a compensatory response to the physiologic stress imposed by the metabolic syndrome and subclinical cardiovascular disease. If this explanation is confirmed, eCO may prove to be an informative, cheap and noninvasive biomarker of cardiometabolic risk. The second potential explanation is that increased eCO levels are in fact pathogenic and lead to clinical cardiovascular disease. In this case, CO may prove to be a valuable drug target. Despite the gaps in our current knowledge, there is considerable evidence supporting an important and potentially causal role for CO in c ardiometabolic disease. In summary, CO has complex relationships with physiological processes, presumably as a function of low versus high concentrations (Supplementary Figure 1; see online at www.futuremedicine.com/doi/full/10.2217/FCA.14.78). These data raise the possibility of a narrow range of CO that is conducive to better health, with opposite effects being observed when a putative threshold is crossed. Further studies are needed to elucidate whether CO concentrations can be used clinically as a biomarker of cardiometabolic risk or a target of drug therapy.
Editorial
“The relationships between exhaled CO concentrations and other cardiovascular-related outcomes, such as chronic kidney disease and heart failure, have yet to be evaluated...”
Financial & competing interests disclosure This work was supported by NIH grant T32-HL007604 (M Nayor) and by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contract N01-HC-25195). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
11
Editorial Nayor & Vasan endothelial cell apoptosis by inhibiting reactive oxygen species formation. J. Biol. Chem. 282(3), 1718–1726 (2007).
References Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
Szabo C. Gaseotransmitters: new frontiers for translational science. Sci. Transl. Med. 2(59), 59ps54 (2010).
2
Owens EO. Endogenous carbon monoxide production in disease. Clin. Biochem. 43(15), 1183–1188 (2010).
•• Excellent review of the function of carbon monoxide in several disease states. 3
4
Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl Acad. Sci. USA 94(20), 10925–10930 (1997). Yachie A, Niida Y, Wada T et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 103(1), 129–135 (1999).
5
Wegiel B, Gallo DJ, Raman KG et al. Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation 121(4), 537–548 (2010).
6
Otterbein LE, Zuckerbraun BS, Haga M et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat. Med. 9(2), 183–190 (2003).
7
•
8
12
True AL, Olive M, Boehm M et al. Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide. Circ. Res. 101(9), 893–901 (2007). Description of the protective role of carbon monoxide on endothelial function and thrombosis. Wang X, Wang Y, Kim HP, Nakahira K, Ryter SW, Choi AM. Carbon monoxide protects against hyperoxia-induced
9
Hosick PA, Alamodi AA, Storm MV et al. Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. Int. J. Obes. (Lond.) 38(1), 132–139 (2014).
10 Thorup C, Jones CL, Gross SS, Moore LC,
Goligorsky MS. Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS. Am. J. Physiol. 277(6 Pt 2), F882–F889 (1999). •
Investigation of the concentrationdependent relationship between carbon monoxide and nitric oxide.
11 Johnson FK, Johnson RA, Durante W,
Jackson KE, Stevenson BK, Peyton KJ. Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290(3), R601–R608 (2006). 12 Henningsson R, Alm P, Ekström P,
Lundquist I. Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. Diabetes 48(1), 66–76 (1999). 13 Thom SR, Xu YA, Ischiropoulos H. Vascular
endothelial cells generate peroxynitrite in response to carbon monoxide exposure. Chem. Res. Toxicol. 10(9), 1023–1031 (1997). 14 Motterlini R, Gonzales A, Foresti R, Clark
JE, Green CJ, Winslow RM. Heme oxygenase-1 derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ. Res. 83(5), 568–577 (1998).
Future Cardiol. (2015) 11(1)
15 Cheng S, Lyass A, Massaro JM, O’connor
GT, Keaney JF Jr, Vasan RS. Exhaled carbon monoxide and risk of metabolic syndrome and cardiovascular disease in the community. Circulation 122(15), 1470–1477 (2010). •• Population-based study of the relationships between exhaled carbon monoxide levels, the metabolic syndrome and incident cardiovascular disease. 16 Zhang J, Yao X, Yu R et al. Exhaled carbon
monoxide in asthmatics: a meta-analysis. Respir. Res. 11, 50 (2010). 17 Scharte M, Bone HG, Van Aken H, Meyer
J. Increased carbon monoxide in exhaled air of critically ill patients. Biochem. Biophys. Res. Commun. 267(1), 423–426 (2000). 18 Paredi P, Biernacki W, Invernizzi G,
Kharitonov SA, Barnes PJ. Exhaled carbon monoxide levels elevated in diabetes and correlated with glucose concentration in blood: a new test for monitoring the disease? Chest 116(4), 1007–1011 (1999). 19 Cheng S, Enserro D, Xanthakis V et al.
Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes. Eur. Heart J. 35(42), 2980–2987 (2014). •• Investigation of the associations between exhaled carbon monoxide, subclinical cardiovascular disease and clinical cardiovascular events in a community-based cohort. 20 Puett RC, Schwartz J, Hart JE et al.
Chronic particulate exposure, mortality, and coronary heart disease in the Nurses’ Health Study. Am. J. Epidemiol. 168(10), 1161–1168 (2008).
future science group
