Vascular Dysfunction and Chronic Obstructive Pulmonary Disease: The Role of Redox Balance

Stephen J Ives; Ryan A. Harris; Melissa A H Witman; Melissa A H Fjeldstad; Ryan S Garten; John McDaniel; D Walter Wray; Russell S Richardson

doi:10.1161/HYPERTENSIONAHA.113.02255

Vascular Dysfunction and Chronic Obstructive Pulmonary Disease: The Role of Redox Balance

Stephen J Ives, Ryan A. Harris, Melissa A H Witman, Melissa A H Fjeldstad, Ryan S Garten, John McDaniel, D Walter Wray, Russell S Richardson

Research output: Contribution to journal › Article › peer-review

75 Citations (Scopus)

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by low pulmonary function, inflammation, free radical production, vascular dysfunction, and subsequently a greater incidence of cardiovascular disease. By administering an acute oral antioxidant cocktail to patients with COPD (n=30) and controls (n=30), we sought to determine the role of redox balance in the vascular dysfunction of these patients. Using a double-blind, randomized, placebo-controlled, crossover design, patients with COPD and controls were ingested placebo or the antioxidant cocktail (vitamin C, vitamin E, α-lipoic acid) after which brachial artery flow-mediated dilation and carotid-radial pulse wave velocity were assessed using ultrasound Doppler. The patients exhibited lower baseline antioxidant levels (vitamin C and superoxide dismutase activity) and higher levels of oxidative stress (thiobarbituic acid reactive species) in comparison with controls. The patients also displayed lower basal flow-mediated dilation (P0.05; placebo versus antioxidant cocktail). The antioxidant cocktail also improved pulse wave velocity in patients with COPD (14±1 versus 11±1 m·s−1; P0.05; placebo versus antioxidant). Patients with COPD exhibit vascular dysfunction, likely mediated by an altered redox balance, which can be acutely mitigated by an oral antioxidant. Therefore, free radically mediated vascular dysfunction may be an important mechanism contributing to this population’s greater risk and incidence of cardiovascular disease.

Original language	English
Journal	Hypertension
Volume	63
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.113.02255
Publication status	Published (in print/issue) - 9 Dec 2013

Bibliographical note

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9. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.
10. Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flowmediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115:2390–2397.
11. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation. 2009;120:502–509.
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Keywords

free radicals
oxidative stress
pulmonary disease
chronic obstructive
vascular stiffness

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1161/HYPERTENSIONAHA.113.02255

http://uir.ulster.ac.uk/28792/1/Ives_-_Harris_2014_COPD_and_AOC.pdf

Cite this

@article{bfbf41cabf174b53bcc7bdb8f54badbc,

title = "Vascular Dysfunction and Chronic Obstructive Pulmonary Disease: The Role of Redox Balance",

abstract = "Chronic obstructive pulmonary disease (COPD) is characterized by low pulmonary function, inflammation, free radical production, vascular dysfunction, and subsequently a greater incidence of cardiovascular disease. By administering an acute oral antioxidant cocktail to patients with COPD (n=30) and controls (n=30), we sought to determine the role of redox balance in the vascular dysfunction of these patients. Using a double-blind, randomized, placebo-controlled, crossover design, patients with COPD and controls were ingested placebo or the antioxidant cocktail (vitamin C, vitamin E, α-lipoic acid) after which brachial artery flow-mediated dilation and carotid-radial pulse wave velocity were assessed using ultrasound Doppler. The patients exhibited lower baseline antioxidant levels (vitamin C and superoxide dismutase activity) and higher levels of oxidative stress (thiobarbituic acid reactive species) in comparison with controls. The patients also displayed lower basal flow-mediated dilation (P0.05; placebo versus antioxidant cocktail). The antioxidant cocktail also improved pulse wave velocity in patients with COPD (14±1 versus 11±1 m·s−1; P0.05; placebo versus antioxidant). Patients with COPD exhibit vascular dysfunction, likely mediated by an altered redox balance, which can be acutely mitigated by an oral antioxidant. Therefore, free radically mediated vascular dysfunction may be an important mechanism contributing to this population{\textquoteright}s greater risk and incidence of cardiovascular disease.",

keywords = "free radicals, oxidative stress, pulmonary disease, chronic obstructive, vascular stiffness",

author = "Ives, {Stephen J} and Harris, {Ryan A.} and Witman, {Melissa A H} and Fjeldstad, {Melissa A H} and Garten, {Ryan S} and John McDaniel and Wray, {D Walter} and Richardson, {Russell S}",

note = "Reference text: 1. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G, Celli B; BODE Collaborative Group. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186:155–161. 2. Macnee W, Maclay J, McAllister D. Cardiovascular injury and repair in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5:824–833. 3. Konecny T, Somers K, Orban M, Koshino Y, Lennon RJ, Scanlon PD, Rihal CS. Interactions between COPD and outcomes after percutaneous coronary intervention. Chest. 2010;138:621–627. 4. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33:1165–1185. 5. Luppi F, Franco F, Begh{\'e} B, Fabbri LM. Treatment of chronic obstructive pulmonary disease and its comorbidities. Proc Am Thorac Soc. 2008;5:848–856. 6. Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest. 2005;127:1952–1959. 7. Matsuoka S, Yamashiro T, Diaz A, Est{\'e}par RS, Ross JC, Silverman EK, Kobayashi Y, Dransfield MT, Bartholmai BJ, Hatabu H, Washko GR. The relationship between small pulmonary vascular alteration and aortic atherosclerosis in chronic obstructive pulmonary disease: quantitative CT analysis. Acad Radiol. 2011;18:40–46. 8. Stone IS, Barnes NC, Petersen SE. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart. 2012;98:1055–1062. 9. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115. 10. Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flowmediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115:2390–2397. 11. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation. 2009;120:502–509. 12. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–1241. 13. Yeboah J, Sutton-Tyrrell K, Mcburnie M, Burke G, Herrington D, Crouse J. Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. Atherosclerosis. 2008;197:768–776. 14. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–1327. 15. Chirinos JA, Kips JG, Jacobs DR Jr, Brumback L, Duprez DA, Kronmal R, Bluemke DA, Townsend RR, Vermeersch S, Segers P. Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012;60:2170–2177. 16. Weber T, Auer J, O{\textquoteright}Rourke MF, Kvas E, Lassnig E, Berent R, Eber B. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation. 2004;109:184–189. 17. Ozben B, Ery{\"u}ksel E, Tanrikulu AM, Papila-Topal N, Celikel T, Ba{\c s}aran Y. Acute exacerbation impairs endothelial function in patients with chronic obstructive pulmonary disease. Turk Kardiyol Dern Ars. 2010;38:1–7. 18. Eickhoff P, Valipour A, Kiss D, Schreder M, Cekici L, Geyer K, Kohansal R, Burghuber OC. Determinants of systemic vascular function in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178:1211–1218. 19. Barr RG, Mesia-Vela S, Austin JHM, Basner RC, Keller BM, Reeves AP, Shimbo D, Stevenson L. Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers. Am J Respir Crit Care Med 2007;176:1200–1207. 20. Maclay JD, McAllister DA, Mills NL, Paterson FP, Ludlam CA, Drost EM, Newby DE, Macnee W. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180:513–520. 21. Maclay JD, McAllister DA, Rabinovich R, Haq I, Maxwell S, Hartland S, Connell M, Murchison JT, van Beek EJ, Gray RD, Mills NL, Macnee W. Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax. 2012;67:606–612. 22. Vivodtzev I, Minet C, Wuyam B, Borel JC, Vottero G, Monneret D, Baguet JP, L{\'e}vy P, P{\'e}pin JL. Significant improvement in arterial stiffness after endurance training in patients with COPD. Chest. 2010;137:585–592. 23. Alford SK, van Beek EJ, McLennan G, Hoffman EA. Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers. Proc Natl Acad Sci U S A. 2010;107:7485–7490. 24. Arao T, Takabatake N, Sata M, Abe S, Shibata Y, Honma T, Takahashi K, Okada A, Takeishi Y, Kubota I. In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)I-metaiodobenzylguanidine. J Nucl Med. 2003;44:1747–1754. 25. Peinado VI, Barbera JA, Ramirez J, Gomez FP, Roca J, Jover L, Gimferrer JM, Rodriguez-Roisin R. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol. 1998;274(6 Pt 1):L908–L913. 26. Chao J, Wood JG, Gonzalez NC. Alveolar macrophages initiate the systemic microvascular inflammatory response to alveolar hypoxia. Respir Physiol Neurobiol. 2011;178:439–448. 27. Sabit R, Shale DJ. Vascular structure and function in chronic obstructive pulmonary disease: a chicken and egg issue? Am J Respir Crit Care Med. 2007;176:1175–1176. 28. Folchini F, Nonato NL, Feofiloff E, D{\textquoteright}Almeida V, Nascimento O, Jardim JR. Association of oxidative stress markers and C-reactive protein with multidimensional indexes in COPD. Chron Respir Dis. 2011;8:101–108. 29. Eagan TM, Ueland T, Wagner PD, Hardie JA, Mollnes TE, Dam{\aa}s JK, Aukrust P, Bakke PS. Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study. Eur Respir J. 2010;35:540–548. 30. Pinto-Plata VM, M{\"u}llerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax. 2006;61:23–28. 31. Celli BR, Locantore N, Yates J, et al; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065–1072. 32. Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, Agust{\'i} AG. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax. 2001;56:432–437. 33. Wray DW, Nishiyama SK, Harris RA, Zhao J, McDaniel J, Fjeldstad AS, Witman MA, Ives SJ, Barrett-O{\textquoteright}Keefe Z, Richardson RS. Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension. 2012;59:818–824. 34. Wray DW, Uberoi A, Lawrenson L, Bailey DM, Richardson RS. Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome. Clin Sci (Lond). 2009;116:433–441. 35. Witman MA, Fjeldstad AS, McDaniel J, Ives SJ, Zhao J, Barrett-O{\textquoteright}Keefe Z, Nativi JN, Stehlik J, Wray DW, Richardson RS. Vascular function and the role of oxidative stress in heart failure, heart transplant, and beyond. Hypertension. 2012;60:659–668. 36. Berg D, Youdim MB, Riederer P. Redox imbalance. Cell Tissue Res. 2004;318:201–213. 37. Ijzerman RG, Serne EH, van Weissenbruch MM, de Jongh RT, Stehouwer CD. Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci (Lond). 2003;104:247–252. 38. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/ WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256–1276. 39. Richardson RS, Donato AJ, Uberoi A, Wray DW, Lawrenson L, Nishiyama S, Bailey DM. Exercise-induced brachial artery vasodilation: role of free radicals. Am J Physiol Heart Circ Physiol. 2007;292:H1516–H1522. 40. Harris RA, Nishiyama SK, Wray DW, Richardson RS. Ultrasound assessment of flow-mediated dilation. Hypertension. 2010;55:1075–1085. 41. Zhang M, Bai Y, Ye P, Luo L, Xiao W, Wu H, Liu D. Type 2 diabetes is associated with increased pulse wave velocity measured at different sites of the arterial system but not augmentation index in a Chinese population. Clin Cardiol. 2011;34:622–627. 42. McEleavy OD, McCallum RW, Petrie JR, Small M, Connell JM, Sattar N, Cleland SJ. Higher carotid-radial pulse wave velocity in healthy offspring of patients with Type 2 diabetes. Diabet Med. 2004;21:262–266. 43. Baguet JP, Kingwell BA, Dart AL, Shaw J, Ferrier KE, Jennings GL. Analysis of the regional pulse wave velocity by Doppler: methodology and reproducibility. J Hum Hypertens. 2003;17:407–412. 44. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588–2605. 45. Reference Values for Arterial Stiffness C. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: {\textquoteleft}Establishing normal and reference values{\textquoteright}. Eur Heart J. 2010;31:2338–2350. 46. Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, Creager MA. Postischemic vasodilation in human forearm is dependent on endotheliumderived nitric oxide. Am J Physiol. 1996;270(4 Pt 2):H1435–H1440. 47. Huang AL, Silver AE, Shvenke E, et al. Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol. 2007;27:2113–2119. 48. Mitchell GF, Parise H, Vita JA, Larson MG, Warner E, Keaney JF Jr, Keyes MJ, Levy D, Vasan RS, Benjamin EJ. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension. 2004;44:134–139. 49. Pyke KE, Dwyer EM, Tschakovsky ME. Impact of controlling shear rate on flow-mediated dilation responses in the brachial artery of humans. J Appl Physiol (1985). 2004;97:499–508. 50. Naka KK, Tweddel AC, Doshi SN, Goodfellow J, Henderson AH. Flowmediated changes in pulse wave velocity: a new clinical measure of endothelial function. Eur Heart J. 2006;27:302–309. 51. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension. 2001;38:1049–1053. 52. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation. 2002;105:213–217. 53. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med. 1996;154(4 Pt 1):1055–1060. 54. Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:29–38. 55. Arthur JR. The glutathione peroxidases. Cell Mol Life Sci. 2000;57:1825–1835. 56. Silvestro A, Scopacasa F, Oliva G, de Cristofaro T, Iuliano L, Brevetti G. Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis. 2002;165:277–283. 57. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003;278:22546–22554. 58. Somers MJ, Mavromatis K, Galis ZS, Harrison DG. Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation. 2000;101:1722–1728. 59. Schmidt TS, Alp NJ. Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease. Clin Sci (Lond). 2007;113:47–63. 60. Crabtree MJ, Tatham AL, Al-Wakeel Y, Warrick N, Hale AB, Cai S, Channon KM, Alp NJ. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cellswith tet-regulated GTP cyclohydrolase I expression. J Biol Chem. 2009;284:1136–1144. 61. V{\'a}squez-Vivar J, Mart{\'a}sek P, Whitsett J, Joseph J, Kalyanaraman B. The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. Biochem J. 2002;362(Pt 3):733–739. 62. Ramsey MW, Goodfellow J, Jones CJ, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation. 1995;92:3212–3219. 63. Donato AJ, Uberoi A, Bailey DM, Wray DW, Richardson RS. Exerciseinduced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men. Am J Physiol Heart Circ Physiol. 2010;298:H671–H678. 64. Jialal I, Devaraj S. Antioxidants and atherosclerosis: don{\textquoteright}t throw out the baby with the bath water. Circulation. 2003;107:926–928. 65. Thomson MJ, Puntmann V, Kaski JC. Atherosclerosis and oxidant stress: the end of the road for antioxidant vitamin treatment? Cardiovasc Drugs Ther. 2007;21:195–210. 66. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781–786. 67. Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang J, Selzer RH, Azen SP; VEAPS Research Group. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002;106:1453–1459. 68. Queiroz TM, Guimar{\~a}es DD, Mendes-Junior LG, Braga VA. α-lipoic acid reduces hypertension and increases baroreflex sensitivity in renovascular hypertensive rats. Molecules. 2012;17:13357–13367.",

year = "2013",

month = dec,

day = "9",

doi = "10.1161/HYPERTENSIONAHA.113.02255",

language = "English",

volume = "63",

journal = "Hypertension",

issn = "1524-4563",

publisher = "American Heart Association",

}

TY - JOUR

T1 - Vascular Dysfunction and Chronic Obstructive Pulmonary Disease: The Role of Redox Balance

AU - Ives, Stephen J

AU - Harris, Ryan A.

AU - Witman, Melissa A H

AU - Fjeldstad, Melissa A H

AU - Garten, Ryan S

AU - McDaniel, John

AU - Wray, D Walter

AU - Richardson, Russell S

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Determinants of systemic vascular function in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178:1211–1218. 19. Barr RG, Mesia-Vela S, Austin JHM, Basner RC, Keller BM, Reeves AP, Shimbo D, Stevenson L. Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers. Am J Respir Crit Care Med 2007;176:1200–1207. 20. Maclay JD, McAllister DA, Mills NL, Paterson FP, Ludlam CA, Drost EM, Newby DE, Macnee W. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180:513–520. 21. Maclay JD, McAllister DA, Rabinovich R, Haq I, Maxwell S, Hartland S, Connell M, Murchison JT, van Beek EJ, Gray RD, Mills NL, Macnee W. Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax. 2012;67:606–612. 22. Vivodtzev I, Minet C, Wuyam B, Borel JC, Vottero G, Monneret D, Baguet JP, Lévy P, Pépin JL. Significant improvement in arterial stiffness after endurance training in patients with COPD. Chest. 2010;137:585–592. 23. Alford SK, van Beek EJ, McLennan G, Hoffman EA. Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers. Proc Natl Acad Sci U S A. 2010;107:7485–7490. 24. Arao T, Takabatake N, Sata M, Abe S, Shibata Y, Honma T, Takahashi K, Okada A, Takeishi Y, Kubota I. In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)I-metaiodobenzylguanidine. J Nucl Med. 2003;44:1747–1754. 25. Peinado VI, Barbera JA, Ramirez J, Gomez FP, Roca J, Jover L, Gimferrer JM, Rodriguez-Roisin R. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol. 1998;274(6 Pt 1):L908–L913. 26. Chao J, Wood JG, Gonzalez NC. Alveolar macrophages initiate the systemic microvascular inflammatory response to alveolar hypoxia. Respir Physiol Neurobiol. 2011;178:439–448. 27. Sabit R, Shale DJ. Vascular structure and function in chronic obstructive pulmonary disease: a chicken and egg issue? Am J Respir Crit Care Med. 2007;176:1175–1176. 28. Folchini F, Nonato NL, Feofiloff E, D’Almeida V, Nascimento O, Jardim JR. Association of oxidative stress markers and C-reactive protein with multidimensional indexes in COPD. Chron Respir Dis. 2011;8:101–108. 29. Eagan TM, Ueland T, Wagner PD, Hardie JA, Mollnes TE, Damås JK, Aukrust P, Bakke PS. Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study. Eur Respir J. 2010;35:540–548. 30. Pinto-Plata VM, Müllerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax. 2006;61:23–28. 31. Celli BR, Locantore N, Yates J, et al; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065–1072. 32. Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, Agustí AG. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax. 2001;56:432–437. 33. Wray DW, Nishiyama SK, Harris RA, Zhao J, McDaniel J, Fjeldstad AS, Witman MA, Ives SJ, Barrett-O’Keefe Z, Richardson RS. Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension. 2012;59:818–824. 34. Wray DW, Uberoi A, Lawrenson L, Bailey DM, Richardson RS. Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome. Clin Sci (Lond). 2009;116:433–441. 35. Witman MA, Fjeldstad AS, McDaniel J, Ives SJ, Zhao J, Barrett-O’Keefe Z, Nativi JN, Stehlik J, Wray DW, Richardson RS. Vascular function and the role of oxidative stress in heart failure, heart transplant, and beyond. Hypertension. 2012;60:659–668. 36. Berg D, Youdim MB, Riederer P. Redox imbalance. Cell Tissue Res. 2004;318:201–213. 37. Ijzerman RG, Serne EH, van Weissenbruch MM, de Jongh RT, Stehouwer CD. Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci (Lond). 2003;104:247–252. 38. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/ WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256–1276. 39. Richardson RS, Donato AJ, Uberoi A, Wray DW, Lawrenson L, Nishiyama S, Bailey DM. Exercise-induced brachial artery vasodilation: role of free radicals. Am J Physiol Heart Circ Physiol. 2007;292:H1516–H1522. 40. Harris RA, Nishiyama SK, Wray DW, Richardson RS. Ultrasound assessment of flow-mediated dilation. Hypertension. 2010;55:1075–1085. 41. Zhang M, Bai Y, Ye P, Luo L, Xiao W, Wu H, Liu D. Type 2 diabetes is associated with increased pulse wave velocity measured at different sites of the arterial system but not augmentation index in a Chinese population. Clin Cardiol. 2011;34:622–627. 42. McEleavy OD, McCallum RW, Petrie JR, Small M, Connell JM, Sattar N, Cleland SJ. Higher carotid-radial pulse wave velocity in healthy offspring of patients with Type 2 diabetes. Diabet Med. 2004;21:262–266. 43. Baguet JP, Kingwell BA, Dart AL, Shaw J, Ferrier KE, Jennings GL. Analysis of the regional pulse wave velocity by Doppler: methodology and reproducibility. J Hum Hypertens. 2003;17:407–412. 44. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588–2605. 45. Reference Values for Arterial Stiffness C. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘Establishing normal and reference values’. Eur Heart J. 2010;31:2338–2350. 46. Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, Creager MA. Postischemic vasodilation in human forearm is dependent on endotheliumderived nitric oxide. Am J Physiol. 1996;270(4 Pt 2):H1435–H1440. 47. Huang AL, Silver AE, Shvenke E, et al. Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol. 2007;27:2113–2119. 48. Mitchell GF, Parise H, Vita JA, Larson MG, Warner E, Keaney JF Jr, Keyes MJ, Levy D, Vasan RS, Benjamin EJ. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension. 2004;44:134–139. 49. Pyke KE, Dwyer EM, Tschakovsky ME. Impact of controlling shear rate on flow-mediated dilation responses in the brachial artery of humans. J Appl Physiol (1985). 2004;97:499–508. 50. Naka KK, Tweddel AC, Doshi SN, Goodfellow J, Henderson AH. Flowmediated changes in pulse wave velocity: a new clinical measure of endothelial function. Eur Heart J. 2006;27:302–309. 51. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension. 2001;38:1049–1053. 52. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation. 2002;105:213–217. 53. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med. 1996;154(4 Pt 1):1055–1060. 54. Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:29–38. 55. Arthur JR. The glutathione peroxidases. Cell Mol Life Sci. 2000;57:1825–1835. 56. Silvestro A, Scopacasa F, Oliva G, de Cristofaro T, Iuliano L, Brevetti G. Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis. 2002;165:277–283. 57. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003;278:22546–22554. 58. Somers MJ, Mavromatis K, Galis ZS, Harrison DG. Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation. 2000;101:1722–1728. 59. Schmidt TS, Alp NJ. Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease. Clin Sci (Lond). 2007;113:47–63. 60. Crabtree MJ, Tatham AL, Al-Wakeel Y, Warrick N, Hale AB, Cai S, Channon KM, Alp NJ. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cellswith tet-regulated GTP cyclohydrolase I expression. J Biol Chem. 2009;284:1136–1144. 61. Vásquez-Vivar J, Martásek P, Whitsett J, Joseph J, Kalyanaraman B. The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. Biochem J. 2002;362(Pt 3):733–739. 62. Ramsey MW, Goodfellow J, Jones CJ, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation. 1995;92:3212–3219. 63. Donato AJ, Uberoi A, Bailey DM, Wray DW, Richardson RS. Exerciseinduced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men. Am J Physiol Heart Circ Physiol. 2010;298:H671–H678. 64. Jialal I, Devaraj S. Antioxidants and atherosclerosis: don’t throw out the baby with the bath water. Circulation. 2003;107:926–928. 65. Thomson MJ, Puntmann V, Kaski JC. Atherosclerosis and oxidant stress: the end of the road for antioxidant vitamin treatment? Cardiovasc Drugs Ther. 2007;21:195–210. 66. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781–786. 67. Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang J, Selzer RH, Azen SP; VEAPS Research Group. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002;106:1453–1459. 68. Queiroz TM, Guimarães DD, Mendes-Junior LG, Braga VA. α-lipoic acid reduces hypertension and increases baroreflex sensitivity in renovascular hypertensive rats. Molecules. 2012;17:13357–13367.

PY - 2013/12/9

Y1 - 2013/12/9

N2 - Chronic obstructive pulmonary disease (COPD) is characterized by low pulmonary function, inflammation, free radical production, vascular dysfunction, and subsequently a greater incidence of cardiovascular disease. By administering an acute oral antioxidant cocktail to patients with COPD (n=30) and controls (n=30), we sought to determine the role of redox balance in the vascular dysfunction of these patients. Using a double-blind, randomized, placebo-controlled, crossover design, patients with COPD and controls were ingested placebo or the antioxidant cocktail (vitamin C, vitamin E, α-lipoic acid) after which brachial artery flow-mediated dilation and carotid-radial pulse wave velocity were assessed using ultrasound Doppler. The patients exhibited lower baseline antioxidant levels (vitamin C and superoxide dismutase activity) and higher levels of oxidative stress (thiobarbituic acid reactive species) in comparison with controls. The patients also displayed lower basal flow-mediated dilation (P0.05; placebo versus antioxidant cocktail). The antioxidant cocktail also improved pulse wave velocity in patients with COPD (14±1 versus 11±1 m·s−1; P0.05; placebo versus antioxidant). Patients with COPD exhibit vascular dysfunction, likely mediated by an altered redox balance, which can be acutely mitigated by an oral antioxidant. Therefore, free radically mediated vascular dysfunction may be an important mechanism contributing to this population’s greater risk and incidence of cardiovascular disease.

AB - Chronic obstructive pulmonary disease (COPD) is characterized by low pulmonary function, inflammation, free radical production, vascular dysfunction, and subsequently a greater incidence of cardiovascular disease. By administering an acute oral antioxidant cocktail to patients with COPD (n=30) and controls (n=30), we sought to determine the role of redox balance in the vascular dysfunction of these patients. Using a double-blind, randomized, placebo-controlled, crossover design, patients with COPD and controls were ingested placebo or the antioxidant cocktail (vitamin C, vitamin E, α-lipoic acid) after which brachial artery flow-mediated dilation and carotid-radial pulse wave velocity were assessed using ultrasound Doppler. The patients exhibited lower baseline antioxidant levels (vitamin C and superoxide dismutase activity) and higher levels of oxidative stress (thiobarbituic acid reactive species) in comparison with controls. The patients also displayed lower basal flow-mediated dilation (P0.05; placebo versus antioxidant cocktail). The antioxidant cocktail also improved pulse wave velocity in patients with COPD (14±1 versus 11±1 m·s−1; P0.05; placebo versus antioxidant). Patients with COPD exhibit vascular dysfunction, likely mediated by an altered redox balance, which can be acutely mitigated by an oral antioxidant. Therefore, free radically mediated vascular dysfunction may be an important mechanism contributing to this population’s greater risk and incidence of cardiovascular disease.

KW - free radicals

KW - oxidative stress

KW - pulmonary disease

KW - chronic obstructive

KW - vascular stiffness

U2 - 10.1161/HYPERTENSIONAHA.113.02255

DO - 10.1161/HYPERTENSIONAHA.113.02255

M3 - Article

SN - 1524-4563

VL - 63

JO - Hypertension

JF - Hypertension

ER -

Vascular Dysfunction and Chronic Obstructive Pulmonary Disease: The Role of Redox Balance

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