Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

Summary

More patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease than direct pulmonary complications. Inflammation and oxidative stress, characteristic in COPD, are likely contributors to the reduction in nitric oxide (NO) bioavailability and vascular endothelial dysfunction in COPD patients; however, this has yet to be determined. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in contributing to vascular endothelial dysfunction in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress, both independently, contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD.

Timeline

Start

2010-09

Primary completion

2015-06

Completion

2015-06

Publications

• Background Selvaraj CL, Gurm HS, Gupta R, Ellis SG, Bhatt DL. Chronic obstructive pulmonary disease as a predictor of mortality in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2005 Sep 15;96(6):756-9. doi: 10.1016/j.amjcard.2005.05.016.
• Background Anthonisen NR, Connett JE, Enright PL, Manfreda J; Lung Health Study Research Group. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002 Aug 1;166(3):333-9. doi: 10.1164/rccm.2110093.
• Background Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899-906. doi: 10.1161/01.cir.101.16.1899.
• Background Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000 Mar 7;101(9):948-54. doi: 10.1161/01.cir.101.9.948.
• Background Wheatcroft SB, Williams IL, Shah AM, Kearney MT. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med. 2003 Apr;20(4):255-68. doi: 10.1046/j.1464-5491.2003.00869.x.
• Background Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994 Mar 1;298 ( Pt 2)(Pt 2):249-58. doi: 10.1042/bj2980249. No abstract available.
• Background Green D. Point: Flow-mediated dilation does reflect nitric oxide-mediated endothelial function. J Appl Physiol (1985). 2005 Sep;99(3):1233-4; discussion 1237-8. doi: 10.1152/japplphysiol.00601.2005. No abstract available.
• Background Uehata A, Lieberman EH, Gerhard MD, Anderson TJ, Ganz P, Polak JF, Creager MA, Yeung AC. Noninvasive assessment of endothelium-dependent flow-mediated dilation of the brachial artery. Vasc Med. 1997;2(2):87-92. doi: 10.1177/1358863X9700200203.
• Background 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 Nov 7;340(8828):1111-5. doi: 10.1016/0140-6736(92)93147-f.
• Background Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation. 2003 Oct 28;108(17):2054-9. doi: 10.1161/01.CIR.0000089191.72957.ED. No abstract available.
• Background Maiorana A, O'Driscoll G, Taylor R, Green D. Exercise and the nitric oxide vasodilator system. Sports Med. 2003;33(14):1013-35. doi: 10.2165/00007256-200333140-00001.
• Background Edwards DG, Schofield RS, Lennon SL, Pierce GL, Nichols WW, Braith RW. Effect of exercise training on endothelial function in men with coronary artery disease. Am J Cardiol. 2004 Mar 1;93(5):617-20. doi: 10.1016/j.amjcard.2003.11.032.
• Background Guerci B, Kearney-Schwartz A, Bohme P, Zannad F, Drouin P. Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function. Diabetes Metab. 2001 Sep;27(4 Pt 1):425-34.
• Background Zarubina EG, Mishina EA, Osadchuk MA. [The role of endothelial dysfunction in the pathogenesis of combined cardiopulmonary diseases]. Klin Med (Mosk). 2006;84(5):31-4. Russian.
• Background Barr RG, Mesia-Vela S, Austin JH, 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: the Emphysema and Cancer Action Project (EMCAP) Study. Am J Respir Crit Care Med. 2007 Dec 15;176(12):1200-7. doi: 10.1164/rccm.200707-980OC. Epub 2007 Aug 29.
• Background Moro L, Pedone C, Scarlata S, Malafarina V, Fimognari F, Antonelli-Incalzi R. Endothelial dysfunction in chronic obstructive pulmonary disease. Angiology. 2008 Jun-Jul;59(3):357-64. doi: 10.1177/0003319707306141. Epub 2008 Apr 2.
• Background 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 Dec 15;178(12):1211-8. doi: 10.1164/rccm.200709-1412OC. Epub 2008 Oct 3.
• Background Fukai T. Endothelial GTPCH in eNOS uncoupling and atherosclerosis. Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1493-5. doi: 10.1161/ATVBAHA.107.148239. No abstract available.
• Background Channon KM. Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med. 2004 Nov;14(8):323-7. doi: 10.1016/j.tcm.2004.10.003.
• Background Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Munzel T. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. Circ Res. 2000 Feb 4;86(2):E36-41. doi: 10.1161/01.res.86.2.e36.
• Background Nandi M, Miller A, Stidwill R, Jacques TS, Lam AA, Haworth S, Heales S, Vallance P. Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse. Circulation. 2005 Apr 26;111(16):2086-90. doi: 10.1161/01.CIR.0000163268.32638.F4. Epub 2005 Apr 11.
• Background Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, Wilkins MR, Channon KM. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation. 2005 Apr 26;111(16):2126-33. doi: 10.1161/01.CIR.0000162470.26840.89. Epub 2005 Apr 11.
• Background Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997 Apr 10;336(15):1066-71. doi: 10.1056/NEJM199704103361506. No abstract available.
• Background De Boer WI. Cytokines and therapy in COPD: a promising combination? Chest. 2002 May;121(5 Suppl):209S-218S. doi: 10.1378/chest.121.5_suppl.209s.
• Background Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med. 1996 Feb;153(2):530-4. doi: 10.1164/ajrccm.153.2.8564092.
• Background Shapiro SD, Senior RM. Matrix metalloproteinases. Matrix degradation and more. Am J Respir Cell Mol Biol. 1999 Jun;20(6):1100-2. doi: 10.1165/ajrcmb.20.6.f151. No abstract available.
• Background Read MA, Whitley MZ, Williams AJ, Collins T. NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation. J Exp Med. 1994 Feb 1;179(2):503-12. doi: 10.1084/jem.179.2.503.
• Background Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998 Nov 5;396(6706):77-80. doi: 10.1038/23948.
• Background Atkinson MH, Menard HA, Kalish GH. Assessment of salsalate, a nonacetylated salicylate, in the treatment of patients with arthritis. Clin Ther. 1995 Sep-Oct;17(5):827-37. doi: 10.1016/0149-2918(95)80061-1.
• Background Bombardier C, Peloso PM, Goldsmith CH. Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group. J Rheumatol. 1995 Apr;22(4):617-24.
• Background Pierce GL, Lesniewski LA, Lawson BR, Beske SD, Seals DR. Nuclear factor-kappaB activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation. 2009 Mar 10;119(9):1284-92. doi: 10.1161/CIRCULATIONAHA.108.804294. Epub 2009 Feb 23.
• Background Halliwell B. Free radicals and antioxidants: a personal view. Nutr Rev. 1994 Aug;52(8 Pt 1):253-65. doi: 10.1111/j.1753-4887.1994.tb01453.x.
• Background Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med. 1996 Jan 18;334(3):150-4. doi: 10.1056/NEJM199601183340303.
• Background Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993 Nov;88(5 Pt 1):2149-55. doi: 10.1161/01.cir.88.5.2149.
• Background Raitakari OT, Adams MR, McCredie RJ, Griffiths KA, Celermajer DS. Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults. Ann Intern Med. 1999 Apr 6;130(7):578-81. doi: 10.7326/0003-4819-130-7-199904060-00017.
• Background Macnee W. Pathogenesis of chronic obstructive pulmonary disease. Clin Chest Med. 2007 Sep;28(3):479-513, v. doi: 10.1016/j.ccm.2007.06.008.
• Background Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986 May;250(5 Pt 2):H822-7. doi: 10.1152/ajpheart.1986.250.5.H822.
• Background Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, Weidinger F. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol. 1998 Sep;32(3):711-6. doi: 10.1016/s0735-1097(98)00295-2.
• Background Plantinga Y, Ghiadoni L, Magagna A, Giannarelli C, Franzoni F, Taddei S, Salvetti A. Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients. Am J Hypertens. 2007 Apr;20(4):392-7. doi: 10.1016/j.amjhyper.2006.09.021.
• Background Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol. 2000 Sep;36(3):758-65. doi: 10.1016/s0735-1097(00)00809-3.
• Background Williams TJ, Howard M, Roget J, Esmore DS. Exercise capacity after combined heart-lung transplantation. Transplant Proc. 1992 Oct;24(5):2018. No abstract available.
• Background Richardson RS, Secher NH, Tschakovsky ME, Proctor DN, Wray DW. Metabolic and vascular limb differences affected by exercise, gender, age, and disease. Med Sci Sports Exerc. 2006 Oct;38(10):1792-6. doi: 10.1249/01.mss.0000229568.17284.ab.
• Background Eskurza I, Myerburgh LA, Kahn ZD, Seals DR. Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults. J Physiol. 2005 Nov 1;568(Pt 3):1057-65. doi: 10.1113/jphysiol.2005.092734. Epub 2005 Sep 1.
• Background Ueda S, Matsuoka H, Miyazaki H, Usui M, Okuda S, Imaizumi T. Tetrahydrobiopterin restores endothelial function in long-term smokers. J Am Coll Cardiol. 2000 Jan;35(1):71-5. doi: 10.1016/s0735-1097(99)00523-9.
• Background Padilla J, Harris RA, Fly AD, Rink LD, Wallace JP. A comparison between active- and reactive-hyperaemia-induced brachial artery vasodilation. Clin Sci (Lond). 2006 Mar;110(3):387-92. doi: 10.1042/CS20050328.
• Background Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. JAMA. 1997 Nov 26;278(20):1682-6.
• Background Padilla J, Harris RA, Fly AD, Rink LD, Wallace JP. The effect of acute exercise on endothelial function following a high-fat meal. Eur J Appl Physiol. 2006 Oct;98(3):256-62. doi: 10.1007/s00421-006-0272-z. Epub 2006 Aug 3.
• Background Tsai WC, Li YH, Lin CC, Chao TH, Chen JH. Effects of oxidative stress on endothelial function after a high-fat meal. Clin Sci (Lond). 2004 Mar;106(3):315-9. doi: 10.1042/CS20030227.
• Background Mullen MJ, Kharbanda RK, Cross J, Donald AE, Taylor M, Vallance P, Deanfield JE, MacAllister RJ. Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia. Circ Res. 2001 Feb 2;88(2):145-51. doi: 10.1161/01.res.88.2.145.
• Background Kingwell BA, Formosa M, Muhlmann M, Bradley SJ, McConell GK. Nitric oxide synthase inhibition reduces glucose uptake during exercise in individuals with type 2 diabetes more than in control subjects. Diabetes. 2002 Aug;51(8):2572-80. doi: 10.2337/diabetes.51.8.2572.
• Background Lieberman EH, Gerhard MD, Uehata A, Selwyn AP, Ganz P, Yeung AC, Creager MA. Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol. 1996 Dec 1;78(11):1210-4. doi: 10.1016/s0002-9149(96)00597-8.
• Background Harris RA, Nishiyama SK, Wray DW, Tedjasaputra V, Bailey DM, Richardson RS. The effect of oral antioxidants on brachial artery flow-mediated dilation following 5 and 10 min of ischemia. Eur J Appl Physiol. 2009 Nov;107(4):445-53. doi: 10.1007/s00421-009-1147-x. Epub 2009 Aug 11.
• Background Bleeker MW, Kooijman M, Rongen GA, Hopman MT, Smits P. Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle. J Physiol. 2005 Jun 1;565(Pt 2):685-94. doi: 10.1113/jphysiol.2005.085936. Epub 2005 Mar 31.
• Background Mercier JG, Hokanson JF, Brooks GA. Effects of cyclosporine A on skeletal muscle mitochondrial respiration and endurance time in rats. Am J Respir Crit Care Med. 1995 May;151(5):1532-6. doi: 10.1164/ajrccm.151.5.7735611.
• Background Casaburi R. Skeletal muscle function in COPD. Chest. 2000 May;117(5 Suppl 1):267S-71S. doi: 10.1378/chest.117.5_suppl_1.267s-a.
• Background Harris RA, Padilla J, Rink LD, Wallace JP. Variability of flow-mediated dilation measurements with repetitive reactive hyperemia. Vasc Med. 2006 Feb;11(1):1-6. doi: 10.1191/1358863x06vm641oa.
• Background Harris RA, Padilla J, Hanlon KP, Rink LD, Wallace JP. Reproducibility of the flow-mediated dilation response to acute exercise in overweight men. Ultrasound Med Biol. 2007 Oct;33(10):1579-85. doi: 10.1016/j.ultrasmedbio.2007.04.014. Epub 2007 Jun 27.
• Background Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol. 1997 Feb 1;79(3):350-4. doi: 10.1016/s0002-9149(96)00760-6.
• Background Sander M, Chavoshan B, Victor RG; New Collective Author. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999 Apr;33(4):937-42. doi: 10.1161/01.hyp.33.4.937.
• Background Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008 May;1(1):36-43. doi: 10.1111/j.1752-8062.2008.00026.x.
• Background Bailey DM, Davies B, Young IS, Jackson MJ, Davison GW, Isaacson R, Richardson RS. EPR spectroscopic detection of free radical outflow from an isolated muscle bed in exercising humans. J Appl Physiol (1985). 2003 May;94(5):1714-8. doi: 10.1152/japplphysiol.01024.2002. Epub 2003 Mar 7.
• Rodriguez-Miguelez P, Gregg J, Seigler N, Bass L, Thomas J, Pollock JS, Sullivan JC, Dillard TA, Harris RA. Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. Chest. 2018 Sep;154(3):597-606. doi: 10.1016/j.chest.2018.04.028. Epub 2018 Apr 26.

Drugs

Indications