Particulate Pollution and Endothelial Function
2005; Lippincott Williams & Wilkins; Volume: 111; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.105.540872
ISSN1524-4539
AutoresSanjay Rajagopalan, Qinghua Sun, Lung‐Chi Chen,
Tópico(s)Global Health Care Issues
ResumoHomeCirculationVol. 111, No. 22Particulate Pollution and Endothelial Function Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBParticulate Pollution and Endothelial FunctionDéjà Vu All Over Again in the Air Sanjay Rajagopalan, MD, Qinghua Sun, MD, PhD and Lung Chi Chen, PhD Sanjay RajagopalanSanjay Rajagopalan From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (S.R., Q.S.), and the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY (L.C.C.). , Qinghua SunQinghua Sun From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (S.R., Q.S.), and the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY (L.C.C.). and Lung Chi ChenLung Chi Chen From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (S.R., Q.S.), and the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY (L.C.C.). Originally published7 Jun 2005https://doi.org/10.1161/CIRCULATIONAHA.105.540872Circulation. 2005;111:2869–2871Agrowing body of epidemiological data implicates particulate matter air pollution (PM) as yet another factor in the pathogenesis of cardiovascular disease.1 PM influences susceptibility to hard events and may be particularly harmful to high-risk groups such as people with diabetes, people with hypertension, and people who smoke.2 The synergistic impact of PM in diabetes mellitus is internally consistent with previous observations, demonstrating that risk factors such as hypertension, diabetes, and smoking may potentiate atherosclerosis. Thus, if one were to predict likely pathological mechanisms, recapitulation of some the previously well-characterized pathways through which risk factors such as smoking or diabetes modulate atherosclerosis may be equally applicable to PM-mediated atherogenicity.See p 2913In this issue of Circulation, O'Neill and colleagues demonstrate that antecedent 6-day moving average levels of PM were negatively associated with endothelium-dependent flow-mediated dilation and nitroglycerin-mediated dilation in 269 subjects with diabetes mellitus (type 1, n=45; type 2, n=182) or subjects at risk for developing diabetes (n=42).3 Although the results of the study represent pooled data from 4 trials, the clinical and environmental variables were merged by date to provide startling insights between variations in vasomotor tone and preceding ambient PM levels. The negative association in the type 2 diabetes population (the majority) was striking and, not surprisingly, drove the results of the study. These results are consistent with the recurring observation of impaired large-vessel endothelial function in people with type 2 diabetes.4 Another notable finding in the present study was the effect of PM on nitroglycerin-mediated dilation. These results are similar to previous studies that noted the impact of risk factors such as diabetes on smooth muscle function and could potentially implicate abnormalities in guanylate cyclase–cyclic guanosine monophosphate signaling pathways to PM.4Of the 4 metrics of PM measured in the study (fine particles <2.5 μm in aerodynamic diameter [PM2.5], sulfates, black carbon, and particle number), the associations were strongest between flow-mediated dilation and sulfates (on multivariate analysis) and between nitroglycerin-mediated dilation and PM2.5 for the overall patient population. Black carbon (represents traffic-related sources) correlated negatively with flow-mediated dilation in subjects with diabetes (strongest in the type 2 group), but this association weakened after the inclusion of sulfates (primarily reflects coal-burning power plants) in the model. The authors were careful to adjust for several confounding variables that may have potentially influenced the results (eg, severity of diabetes by HbA1c levels, hormone replacement therapy, alcohol use) and reassuringly demonstrate the consistency of their data even after adjusting for these variables. The results in the type 1 group showed negative but less striking trends, and this may be consistent with a greater impact of type 2 diabetes on endothelial function. Interestingly, the authors report a positive rather than a negative association among PM metrics, flow-mediated dilation, and nitroglycerin-mediated dilation in the "at-risk" group. Although this finding appears to contradict a "graded" effect that impaired glucose tolerance may have on endothelial function, the results may be reconciled by the limited sample size in this group that may have diminished the discriminative ability of their analysis. Another potential methodological issue that may explain some of their associations (or lack thereof) is that ambient air PM metrics (within 500 m of where subjects were examined) were used. These were presumed to reflect personal exposure and this may not necessarily be the case, especially with measures such as black carbon and particle numbers that demonstrate marked spatial variation. It is therefore important, as the authors emphasize, that lack of effect not be construed as representing "lack of evidence" for biological activity. It is conceivable that traffic-related sources and subfractions may still play an important role in modulating vessel wall responses.5How might PM modulate endothelial function? Loss of endothelium-derived nitric oxide (·NO) plays a central role in the pathogenesis of diseases such as smoking-related vascular disease, atherosclerosis, hypertension, and diabetes. The decline in ·NO bioavailability may be caused by multiple abnormalities in the generation of ·NO, including altered expression of the enzyme endothelial nitric oxide synthase, altered function of the enzyme because of the lack of its substrate l-arginine or its cofactor tetrahydrobiopterin (BH4), alterations in cellular signaling such that the enzyme is not activated, and accelerated ·NO destruction by superoxide.6 The latter mechanism is particularly relevant because PM is an important generator of reactive oxygen species (ROS).7–10 Although the precise locus of generation of these radicals is hotly debated, there is reason to believe that the vasculature may be key in mediating and modulating the effects of PM. The endothelium in the lungs is the initial locus of contact for PM, and the smallest particles (PM particles <0.1 μm) have been shown to translocate from the lungs into the circulation, where they may mediate their effects.11 The pathological consequences of PM on the vessel wall can be summarized below, depending on the type of evidence (cellular/biochemical, animals, and human).Cellular and Biochemical Evidence of PM EffectsExposure of endothelial cells to diesel exhaust particles markedly reduces ·NO formation and may potentiate cytotoxicity.7,12 The cytotoxic effects are reversed by superoxide dismutase, catalase, and N-(2-mercaptopropionyl) glycine, implicating a role for superoxide, hydrogen peroxide, and hydroxyl radicals, respectively, in these effects. In these experiments, inhibitors of nitric oxide synthase resulted in an attenuation of diesel exhaust particle–induced endothelial cell damage. Furthermore, treatment with BH4 and ebselen (a peroxynitrite scavenger) also resulted in attenuation of cell damage, suggesting that depletion of BH4 may play a role in nitric oxide synthase–mediated superoxide and peroxynitrite generation.7Data in Animal Models Supporting PM-Mediated Effects on the VasculatureExposure of rats to PM aerosols, even for short durations, results in marked increases in oxidative stress in the heart and lungs, as determined by in situ chemiluminescence.10 Increased indices of oxidant stress are associated with tissue-specific increases (in the myocardium) in antioxidant enzymes, such as superoxide dismutase and catalase consistent with adaptive responses.10 ROS generation in these models shows strong associations with the PM content of iron, manganese, copper, and other trace elements, consistent with the effects of transition metals in facilitating ROS. Recently, short-term exposure to PM in rats has been associated with elevations in asymmetric dimethylarginine (ADMA).13 Although the mechanism for this remains to be elucidated, there is strong evidence that ADMA level is determined by the enzyme dimethylarginine dimethylaminohydrolase.14 Oxidant stress has been shown to regulate dimethylaminohydrolase activity and thus could potentially contribute to an increase in ADMA.14 Another consequence of reduced ·NO is heightened platelet aggregation.15 In animal models, diesel exhaust particles accentuate in vitro measures of platelet aggregation and enhance peripheral thrombosis.16Thus, at least in cultured cells and animals, PM results in increases in oxidative stress, which may then alter bioavailable ·NO levels and result in endothelial dysfunction. The ROS sources activated by PM could vary, dependent on the composition, size, and eventual locus of deposition of the particles within the vessel wall.Data in Humans Supporting PM-Mediated Effects on the VasculatureControlled exposures to PM result in acute responses and may explain susceptibility to cardiovascular events within a few hours of exposure to pollution. A 2-hour exposure of healthy adults to PM2.5 and ozone resulted in conduit artery (brachial) vasoconstriction, but it did not result in diminution of flow-mediated dilation or nitroglycerin dilation.17 Although superficially inconsistent with the O'Neill et al study, these results actually bolster the evidence that PM exposure may alter conduit vessel tone in a time- and dose-dependent manner. The study by Brook et al involved controlled exposure to PM (150 μg/m3 of ambient PM2.5 plus ozone [120 ppb]) in healthy adults. The decrease in conduit vessel diameter in this study is suggestive of a rapid direct effect of PM in diminishing basal ·NO levels, generation of vasoconstrictors such as endothelin-1, or both.18 In contrast, more prolonged exposure, additional abnormalities (predisposition in the form of diabetes, hypertension, and hypercholesterolemia), as was the case in the O'Neill et al study, or both may be required to induce agonist-mediated changes in endothelial function. Increases in inflammatory measures such as C-reactive protein with PM exposure have also been shown and may represent responses to endothelial dysfunction and activation of oxidant stress/cytokine pathways.19Irrespective of the mechanism, decreased bioavailable ·NO levels and endothelial dysfunction are likely to have other, unintended consequences such as activation of the sympathetic system,20 endothelin-1 pathway,18 and an elevation in blood pressure and this in the intermediate and long term may influence vascular morbidity and mortality. Indeed, at least 2 epidemiological studies have suggested an association between PM and an increase in blood pressure. Ibald-Mulli et al reported that total suspended particles and sulfur dioxide levels were associated with a small increase in systolic blood pressure in 2607 adults during an episode of extreme air pollution in southern Germany.21 In a subgroup of individuals with a high heart rate and plasma viscosity, the increase in blood pressure was most dramatic. A similar finding was reported in 66 patients during repeated visits for cardiac rehabilitation in Boston.22 Diastolic pressure increased in relation to the previous 2- and 5-day mean concentrations of PM2.5. Thus, it is possible that PM exposure through alterations in endothelial function, activation of the sympathetic system, endothelin-1 axis, and platelet function may predispose to hypertension and atherosclerosis (Figure). Observational and limited cohort studies need to be confirmed by larger prospectively designed studies that test the hypothesis that PM is deleterious to vascular health. If lessons from hypercholesterolemia, hypertension, and diabetes are at all predictive, then this may be, as Yogi Berra put it, "déjà vu all over again."Download figureDownload PowerPointHypothetical schema of PM-mediated effects on the endothelium and its consequences. ET-1 indicates endothelin-1; HRV, heart rate variability; all other abbreviations as in text.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This work was supported by the following grants: R01 ES013406-01, R827351, and ES 00260 (Environmental Protection Agency and National Institute of Environmental Health Sciences center grants).FootnotesCorrespondence to Sanjay Rajagopalan, MD, Mount Sinai School of Medicine, One Gustave Levy Pl, Box 1030, New York, NY 10029. E-mail [email protected] References 1 Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, Luepker R, Mittleman M, Samet J, Smith SC Jr, Tager I. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation. 2004; 109: 2655–2671.LinkGoogle Scholar2 Pope CA III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation. 2004; 109: 71–77.LinkGoogle Scholar3 O'Neill MS, Veves A, Zanobetti A, Sarnat JA, Gold DR, Economides PA, Horton E, Schwartz J. Diabetes enhances vulnerability to particulate air pollution–associated impairment in vascular reactivity and endothelial function. Circulation. 2005; 111: 2913–2920.LinkGoogle Scholar4 Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E, Halcox J, Kiowski W, Luscher TF, Mancia G, Natali A, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Spieker LE, Taddei S, Webb DJ. Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005; 23: 233–246.CrossrefMedlineGoogle Scholar5 Urch B, Brook JR, Wasserstein D, Brook RD, Rajagopalan S, Corey P, Silverman F. Relative contributions of PM2.5 chemical constituents to acute arterial vasoconstriction in humans. Inhal Toxicol. 2004; 16: 345–352.CrossrefMedlineGoogle Scholar6 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87: 840–844.CrossrefMedlineGoogle Scholar7 Bai Y, Suzuki AK, Sagai M. The cytotoxic effects of diesel exhaust particles on human pulmonary artery endothelial cells in vitro: role of active oxygen species. Free Radic Biol Med. 2001; 30: 555–562.CrossrefMedlineGoogle Scholar8 Dellinger B, Pryor WA, Cueto R, Squadrito GL, Hegde V, Deutsch WA. Role of free radicals in the toxicity of airborne fine particulate matter. Chem Res Toxicol. 2001; 14: 1371–1377.CrossrefMedlineGoogle Scholar9 Han JY, Takeshita K, Utsumi H. Noninvasive detection of hydroxyl radical generation in lung by diesel exhaust particles. Free Radic Biol Med. 2001; 30: 516–525.CrossrefMedlineGoogle Scholar10 Gurgueira SA, Lawrence J, Coull B, Murthy GG, Gonzalez-Flecha B. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation. Environ Health Perspect. 2002; 110: 749–755.CrossrefMedlineGoogle Scholar11 Nemmar A, Hoylaerts MF, Hoet PH, Dinsdale D, Smith T, Xu H, Vermylen J, Nemery B. Ultrafine particles affect experimental thrombosis in an in vivo hamster model. Am J Respir Crit Care Med. 2002; 166: 998–1004.CrossrefMedlineGoogle Scholar12 Ikeda M, Watarai K, Suzuki M, Ito T, Yamasaki H, Sagai M, Tomita T. Mechanism of pathophysiological effects of diesel exhaust particles on endothelial cells. Environ Toxicol Pharmacol. 1998; 6: 117–123.CrossrefMedlineGoogle Scholar13 Dvonch JT, Brook RD, Keeler GJ, Rajagopalan S, D'Alecy LG, Marsik FJ, Morishita M, Yip FY, Brook JR, Timm EJ, Wagner JG, Harkema JR. Effects of concentrated fine ambient particles on rat plasma levels of asymmetric dimethylarginine. Inhal Toxicol. 2004; 16: 473–480.CrossrefMedlineGoogle Scholar14 Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.CrossrefMedlineGoogle Scholar15 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res. 2001; 88: 756–762.CrossrefMedlineGoogle Scholar16 Nemmar A, Hoet PH, Dinsdale D, Vermylen J, Hoylaerts MF, Nemery B. Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis. Circulation. 2003; 107: 1202–1208.LinkGoogle Scholar17 Brook RD, Brook JR, Urch B, Vincent R, Rajagopalan S, Silverman F. Inhalation of fine particulate air pollution and ozone causes acute arterial vasoconstriction in healthy adults. Circulation. 2002; 105: 1534–1536.LinkGoogle Scholar18 Bouthillier L, Vincent R, Goegan P, Adamson IY, Bjarnason S, Stewart M, Guenette J, Potvin M, Kumarathasan P. Acute effects of inhaled urban particles and ozone: lung morphology, macrophage activity, and plasma endothelin-1. Am J Pathol. 1998; 153: 1873–1884.CrossrefMedlineGoogle Scholar19 Peters A, Frohlich M, Doring A, Immervoll T, Wichmann HE, Hutchinson WL, Pepys MB, Koenig W. Particulate air pollution is associated with an acute phase response in men; results from the MONICA-Augsburg Study. Eur Heart J. 2001; 22: 1198–1204.CrossrefMedlineGoogle Scholar20 Magari SR, Hauser R, Schwartz J, Williams PL, Smith TJ, Christiani DC. Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation. 2001; 104: 986–991.CrossrefMedlineGoogle Scholar21 Ibald-Mulli A, Stieber J, Wichmann HE, Koenig W, Peters A. Effects of air pollution on blood pressure: a population-based approach. Am J Public Health. 2001; 91: 571–577.CrossrefMedlineGoogle Scholar22 Zanobetti A, Canner MJ, Stone PH, Schwartz J, Sher D, Eagan-Bengston E, Gates KA, Hartley LH, Suh H, Gold DR. Ambient pollution and blood pressure in cardiac rehabilitation patients. Circulation. 2004; 110: 2184–2189.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Salimi S, Yanosky J, Huang D, Montressor-Lopez J, Vogel R, Reed R, Mitchell B and Puett R (2020) Long-term exposure to particulate air pollution and brachial artery flow-mediated dilation in the Old Order Amish, Environmental Health, 10.1186/s12940-020-00593-y, 19:1, Online publication date: 1-Dec-2020. Al-wasiti E (2019) Assessment of Sewage Workers' Exposure to Hazardous Materials in Iraq, Iraqi National Journal of Medicine, 10.37319/iqnjm.1.1.4, 1:1, (22-38), Online publication date: 28-Jan-2019. Chuang H, Lin Y, Chou C, Hwang J, Chen C, Yan Y, Hsieh H, Chuang K and Cheng T (2017) Alterations in cardiovascular function by particulate matter in rats using a crossover design, Environmental Pollution, 10.1016/j.envpol.2017.08.082, 231, (812-820), Online publication date: 1-Dec-2017. Vieira J, Macedo F, Benjo A, Guimarães G, Contreras J and Bocchi E (2016) Systemic effects of controlled exposure to diesel exhaust: a meta-analysis from randomized controlled trials, Annals of Medicine, 10.1080/07853890.2016.1252054, 49:2, (165-175), Online publication date: 17-Feb-2017. Buckley B and Farraj A (2015) Conceptual model for assessing criteria air pollutants in a multipollutant context: A modified adverse outcome pathway approach, Toxicology, 10.1016/j.tox.2015.07.007, 335, (85-94), Online publication date: 1-Sep-2015. Barbosa S, Farhat S, Martins L, Pereira L, Saldiva P, Zanobetti A and Braga A (2015) Air pollution and children's health: sickle cell disease, Cadernos de Saúde Pública, 10.1590/0102-311X00013214, 31:2, (265-275), Online publication date: 1-Feb-2015. Lin L, Lin H, Chen H, Su T, Huang L and Chuang K (2012) Effects of temple particles on inflammation and endothelial cell response, Science of The Total Environment, 10.1016/j.scitotenv.2011.08.050, 414, (68-72), Online publication date: 1-Jan-2012. Pautrel X (2012) Pollution, Private Investment in Healthcare, and Environmental Policy*, The Scandinavian Journal of Economics, 10.1111/j.1467-9442.2012.01696.x, 114:2, (334-357), Online publication date: 1-Jun-2012. Chuang H, Fan C, Chen K, Chang-Chien G and Chan C (2012) Vasoactive alteration and inflammation induced by polycyclic aromatic hydrocarbons and trace metals of vehicle exhaust particles, Toxicology Letters, 10.1016/j.toxlet.2012.08.012, 214:2, (131-136), Online publication date: 1-Oct-2012. Mathieu-Bolh N and Pautrel X (2011) Taxe environnementale, morbidité et profil de productivité, Revue économique, 10.3917/reco.623.0501, Vol. 62:3, (501-509), Online publication date: 1-May-2011. Zou M (2010) Is NAD(P)H Oxidase a Missing Link for Air Pollution–Enhanced Obesity?, Arteriosclerosis, Thrombosis, and Vascular Biology, 30:12, (2323-2324), Online publication date: 1-Dec-2010. Chuang K, Yan Y and Cheng T (2010) Effect of Air Pollution on Blood Pressure, Blood Lipids, and Blood Sugar: A Population-Based Approach, Journal of Occupational & Environmental Medicine, 10.1097/JOM.0b013e3181ceff7a, 52:3, (258-262), Online publication date: 1-Mar-2010. Saadat S, Sadeghian S, Hamidian R and Najafi M (2010) Air Pollution and In-Hospital Mortality of Ischemic Heart Disease Patients, Journal of Biological Sciences, 10.3923/jbs.2010.117.121, 10:2, (117-121), Online publication date: 1-Feb-2010. Pautrel X Health-Enhancing Activities and the Environment: How Competition for Resources Make the Environmental Policy Beneficial, SSRN Electronic Journal, 10.2139/ssrn.1457365 Sun Q, Yue P, Ying Z, Cardounel A, Brook R, Devlin R, Hwang J, Zweier J, Chen L and Rajagopalan S (2008) Air Pollution Exposure Potentiates Hypertension Through Reactive Oxygen Species-Mediated Activation of Rho/ROCK, Arteriosclerosis, Thrombosis, and Vascular Biology, 28:10, (1760-1766), Online publication date: 1-Oct-2008. Peretz A, Sullivan J, Leotta D, Trenga C, Sands F, Allen J, Carlsten C, Wilkinson C, Gill E and Kaufman J (2008) Diesel Exhaust Inhalation Elicits Acute Vasoconstriction in Vivo , Environmental Health Perspectives, 10.1289/ehp.11027, 116:7, (937-942), Online publication date: 1-Jul-2008. Auchincloss A, Diez Roux A, Dvonch J, Brown P, Barr R, Daviglus M, Goff D, Kaufman J and O'Neill M (2008) Associations between Recent Exposure to Ambient Fine Particulate Matter and Blood Pressure in the Multi-Ethnic Study of Atherosclerosis (MESA), Environmental Health Perspectives, 10.1289/ehp.10899, 116:4, (486-491), Online publication date: 1-Apr-2008. Eisert W and Schlachetzki F (2008) Chapter 10 Vascular endothelium and the blood–brain barrier Stroke, 10.1016/S0072-9752(08)01910-6, (197-214), . Chuang K, Chan C, Su T, Lee C and Tang C (2007) The Effect of Urban Air Pollution on Inflammation, Oxidative Stress, Coagulation, and Autonomic Dysfunction in Young Adults, American Journal of Respiratory and Critical Care Medicine, 10.1164/rccm.200611-1627OC, 176:4, (370-376), Online publication date: 15-Aug-2007. Simkhovich B, Marjoram P, Kleinman M and Kloner R (2007) Direct and acute cardiotoxicity of ultrafine particles in young adult and old rat hearts, Basic Research in Cardiology, 10.1007/s00395-007-0681-0, 102:6, (467-475), Online publication date: 1-Nov-2007. Bhatnagar A (2006) Environmental Cardiology, Circulation Research, 99:7, (692-705), Online publication date: 29-Sep-2006. June 7, 2005Vol 111, Issue 22 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.105.540872PMID: 15939830 Originally publishedJune 7, 2005 Keywordsendotheliumnitric oxideEditorialsmyocardial infarctionfree radicalsPDF download Advertisement SubjectsDiabetes, Type 2Endothelium/Vascular Type/Nitric OxideEtiologyPathophysiologyPlatelets
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