Progress in Cardiovascular Diseases
Volume 46, Issue 1 , Pages 79-90 , July 2003

Oxidative stress and smoking-induced vascular injury

  • Anne Burke

      Affiliations

    • Gastrointestinal Division Philadelphia, PA, USA
  • ,
  • Garret A FitzGerald

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Garret A. FitzGerald, MD, Robinette Professor of Cardiovascular Medicine, Chairman, Department of Pharmacology, 153 Johnson Pavilion, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA
    • Center for Experimental Therapeutics, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

References 

  1. Oxidative stress: adaptation, damage, repair and death. In:  Halliwell B,  Gutteridge JMC editor. Free Radicals in Biology and Medicine. Oxford: Oxford University Press; 1999;p. 346–350
  2. Griendling KK, FitzGerald GA. Oxidative stress and vascular injury. Circulation. 2003; (in press)
  3. Church DF, Pryor WA. Free radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect. 1985;64:111
  4. Detection of free radicals and other reactive species (Trapping and fingerprinting). In:  Halliwell B,  Gutteridge JMC editor. Free Radicals in Biology and Medicine. Oxford: Oxford University Press; 1999;p. 351–429
  5. Esposti MD. Measuring mitochondrial reactive oxygen species. Methods. 2002;26:335–340
  6. Tarpey MM, Fridovich I. Methods of detection of vascular reactive species (Nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite). Circ Res. 2001;89:224–236
  7. Meagher EA, FitzGerald GA. Indices of lipid peroxidation in vivo (Strengths and limitations). Free Radic Biol Med. 2000;28:1745–1750
  8. Hecker M, Haurand M, Ullrich V, et al.  Spectral studies on structure-activity relationships of thromboxane synthase inhibitors. Eur J Biochem. 1986;157:217–223
  9. Morrow JD, Frei B, Longmire AW, et al.  Increase in circulating products of peroxidation (F2-isoprostanes) in smokers. N Engl J Med. 1995;33:1198–1203
  10. Reilly M, Delanty N, Lawson JA, et al.  Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation. 1996;94:19–25
  11. Pilz H, Oguogho A, Chehne F, et al.  Quitting cigarette smoking results in a fast improvement of in vivo oxidation injury (determined via plasma, serum and urinary isoprostanes). Thromb Res. 2000;99:209–221
  12. Obata T, Tomaru K, Nagakura T, et al.  Smoking and oxidant stress (Assay of isoprostane in human urine by gas chromatography-mass spectrometry). J Chromatogr B. 2000;746:11–15
  13. Zhou JF, Yan XF, Guo FZ, et al.  Effects of cigarette smoking and smoking cessation on plasma constituents and enzyme activities related to oxidative stress. Biomed Environ Sci. 2000;13:44–55
  14. Chehne F, Oguogho A, Lupattelli G, et al.  Increase of isoprostane 8-epi-PGF(2alpha) after restarting smoking. Prostaglandins Leukot Essent Fatty Acids. 2001;64:307–310
  15. Pignatelli B, Li CO, Boffetta P, et al.  Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res. 2001;61:778–784
  16. MacMillan-Crow LA, Crow JP, Kerby JD, et al.  Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci U S A. 1996;93:11853–11858
  17. Knight-Lozano CA, Young CG, Burow DL, et al.  Cigarette smoke exposure and hypercholesterolemia increase mitochondrial damage in cardiovascular tissues. Circulation. 2002;105:849–854
  18. Loft S, Poulsen HE. Cancer risk and oxidative DNA damage in man. J Mol Med. 1996;74:297
  19. Howard DJ, Ota RB, Briggs LA, et al.  Oxidative stress induced by environmental tobacco smoke in the workplace is mitigated by antioxidant supplementation. Cancer Epidemiol Biomarkers Prev. 1998;7:981–988
  20. Lee SH, Blair IA. Analysis of etheno 2′-deoxyguanosine adducts as dosimeters of AKR-mediated oxidative stress. In:  Penning TM,  Petrash JM editor. Aldo-Keto Reductases and Toxicant Metabolism. Oxford: Oxford University Press; 2003;
  21. Antioxidant defences. In:  Halliwell B,  Gutteridge JMC editor. Free radicals in biology and medicine. Oxford: Oxford University Press; 1999;p. 105–245
  22. Ghiselli A, Serafini M, Natella F, et al.  Total antioxidant capacity as a tool to assess redox status (Critical view and experimental data). Free Radic Biol Med. 2000;29:1106–1114
  23. Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis (An overview). Free Radic Biol Med. 2000;28:1815–1826
  24. Reilly M, Pratico D, Delanty N, et al.  Increased formation of distinct F2 isoprostanes in hypercholesterolemia. Circulation. 1998;98:2822–2828
  25. De Caterina R, Cipollone F, Filardo FP, et al.  Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects (No further effect of vitamin E). Circulation. 2002;106:2543–2549
  26. Kagota S, Yamaguchi Y, Shinozuka K, et al.  Cigarette smoke-modified low density lipoprotein impairs endothelium-dependent relaxation in isolated rabbit arteries. Gen Pharmacol. 1996;27:447–481
  27. Gouaze V, Dousset N, Dousset JC, et al.  Effect of nicotine and cotinine on the susceptibility to in vitro oxidation of LDL in healthy non smokers and smokers. Clin Chim Act. 1998;277:25–37
  28. Scheffler E, Wiest E, Woehrle J, et al.  Smoking influences the atherogenic potential of low density lipoprotein. Clin Invest. 1992;70:263–265
  29. Siekmeier R, Wilifroth P, Wieland H, Groβ W, et al.  Lowe density lipoprotein susceptibility to in vitro oxidation in healthy smokers and non-smokers. Clin Chem. 1996;42:524–530
  30. Princen HMG, Van Poppel G, Vogeizang C, et al.  Supplementation with vitamin E but not β-carotene in vivo protects low density lipoproteins from lipid peroxidation in vitro. Arterioscler Thromb. 1992;12:554–562
  31. Chen C, Lao G. Cigarette smoke inhibits oxidative modification of low density lipoprotein. Atherosclerosis. 1995;112:177–185
  32. Harats D, Ben-Naim M, Dabach Y, et al.  Cigarette smoking renders LDL susceptible to peroxidative modification and enhanced metabolism by macrophages. Atherosclerosis. 1989;79:245–252
  33. Santanam N, Sanchez R, Hendler S, et al.  Aqueous extracts of cigarette smoke promote the oxidation of low density lipoprotein by peroxidases. FEBS Lett. 1997;414:549–551
  34. Sasaki A, Kondo K, Sakamoto Y, et al.  Smoking cessation increases the resistance of low-density lipoprotein to oxidation. Atherosclerosis. 1997;130:109–111
  35. Tsuchiya M, Asada A, Kasahara E, et al.  Smoking a single cigarette rapidly reduces combined circulations of nitrate and nitrate and the concentrations of antioxidants in plasma. Circulation. 2002;105:1155–1157
  36. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases (The role of oxidant stress). Circ Res. 2000;87:840–844
  37. Vassier-Taussat M, Camilli T, Aron Y, et al.  Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress response. Am J Physiol. 2001;280:H1293–H1300
  38. Kalra VK, Ying Y, Deemer K, et al.  Mechanism of cigarette smoke condensate induced adhesion of human monocytes to cultured endothelial cells. J Cell Physiol. 1994;160:154–162
  39. Weber C, Erl W, Weber K, et al.  Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers. Circulation. 1996;93:1448–1492
  40. Lehr H-A, Frei B, Arfors KE. Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothelium in vivo. Proc Natl Acad Sci USA. 1994;91:7688–7692
  41. Bridges RB, Fu MC, Rehm SR. Increased neutrophil myeloperoxidase activity associated with cigarette smoking. Eur J Respir Dis. 1985;67:84–93
  42. Kannel WB, McGee DL, Castelli WP. Latest perspectives on cigarette smoking and cardiovascular disease. J Card Rehab. 1984;4:267
  43. Fuster V, Chesebro JH, Frye RL, et al.  Platelet survival and the development of coronary artery disease in the young adult (Effects of cigarette smoking, strong family history and medical therapy). Circulation. 1981;63:546–551
  44. Murray JJ, Nowak J, Oates JA, et al.  Biosynthesis of thromboxane A2 and prostacyclin during chronic smoking and withdrawal in man. Clin Res. 1985;33:521A
  45. Wennmalm A, Benthin G, Granstrom E, et al.  Relationship between tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in young men. Circulation. 1991;83:1698–1704
  46. Lassila R, Seyberth HW, Haapanen A, et al.  Vasoactive and atherogenic effects for cigarette smoking (A study of monozygotic twins discordant for smoking). BMJ. 1998;297:955–960
  47. Meade TW, Vickers MV, Thompson SG, et al.  Epidemiological characteristics of platelet aggregability. BMJ. 1985;290:428–432
  48. Freedman JE, Ting B, Hankin B, et al.  Nitric oxide release from activated platelets inhibits platelet recruitment. J Clin Invest. 1997;100:350–356
  49. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide (Physiology, pathophysiology and pharmacology). Pharmacol Rev. 1991;43:109–142
  50. Takajo Y, Ikeda H, Haramaki N, et al.  Augmented oxidative stress of platelets in chronic smokers. J Am Coll Cardiol. 2001;38:1320–1327
  51. Audoly LP, Rocca B, Fabre JE, et al.  Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation. 2000;101:2833–2840
  52. Davi G, Ciabattoni G, Consoli A, et al.  In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus (Effects of improved metabolic control and vitamin E supplementation). Circulation. 1999;99:224–229
  53. Mirshahi F, Vasse M, Vincent L, et al.  Fibrinogen (A vascular risk factor, why? Contributing effect of oncostatin M on both fibrinogen biosynthesis by hepatocytes and participation in atherothrombotic risk related to modification of endothelial cells). Ann N Y Acad Sci. 2001;936:621–624
  54. Wilhelmsen L, Svardsudd K, Korsan-Bengsten K, et al.  Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–505
  55. Stone MC, Thorp JM. Plasma fibrinogen—a major coronary risk factor. J R Coll Gen Pract. 1985;35:565–569
  56. Tuut M, Hense H-W. Smoking, other risk factors and fibrinogen levels (Evidence of effect modification). Ann Epidemiol. 2001;11:232–238
  57. Green TAE, Lamlum H, Humphries SE. The association of combined alpha and beta fibrinogen genotype on plasma fibrinogen levels in smokers and non-smokers. J Med Genet. 1995;32:585–589
  58. Cooke DG, Cappuccio FP, Atkinson RW, et al.  Ethnic differences in fibrinogen levels (The role of environmental factors and the β-fibrinogen gene). Am J Epidemiol. 2001;153:799–806
  59. Gole MD, Souza JM, Choi I, et al.  Plasma proteins modified by tyrosine nitration in acute respiratory syndrome. Am J Physiol. 2000;2278:L961–L967
  60. Sambola A, Osende J, Hathcock J, et al.  Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003;107:973–977
  61. Barua RS, Ambrose JA, Dhanonoy CS, et al.  Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors. An in vitro demonstration. Circulation. 2002;106:905–908
  62. Busacca M, Balconi G, Pietra A, et al.  Maternal smoking and prostacyclin production by culture endothelial cells from umbilical arteries. Am J Obstet Gynecol. 1984;148:1127–1130
  63. Matetzky S, Tani S, Kangavari S, et al.  Smoking increases tissue factor expression in atherosclerotic plaques (Implications for plaque thrombogenicity). Circulation. 2000;102:602–604
  64. Celermajer DS, Sorensen KE, Gooch VM, et al.  Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115
  65. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376
  66. Schachinger V, Britten MB, Zeiber AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899–1906
  67. Barua RS, Ambrose JA, Eales-Reynolds L-J, et al.  Heavy and light cigarette smokers have similar dysfunction of endothelial regulatory activity. J Am Coll Cardiol. 2002;39:1758–1763
  68. Celermajer DS, Sorensen KE, Georgakopoulos D, et al.  Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149–2155 (abstr)
  69. Celermajer DS, Adams MR, Clarkson P, et al.  Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med. 1996;334:150–154
  70. Lekakis J, Papamichael C, Vemmos C, et al.  Effect of acute cigarette smoking on endothelium-dependent brachial artery dilatation in healthy individuals. Am J Cardiol. 1997;79:529–531
  71. Zhang J, Ying X, Lu Q, et al.  A single high dose of vitamin C counteracts the acute negative effect on microcirculation induced by smoking a cigarette. Microvasc Res. 1999;58:305–311
  72. Motoyama T, Kawano H, Kugiyama K, et al.  Endothelium-dependent vasodilation in the brachial artery is impaired in smokers (Effects of vitamin C). Am J Physiol. 1997;273:H1644–H1650
  73. Heitzer T, Just H, Münzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation. 1996;94:6–9
  74. Raitakari OT, Adams MR, McCredie RJ, et al.  Oral vitamin C and endothelial function in smokers (Short-term improvement but no sustained beneficial effect). J Am Coll Cardiol. 2000;25:1616–1621
  75. Heitzer T, Brockhoff C, Mayer B, et al.  Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers (Evidence for a dysfunctional nitric oxide synthase). Circ Res. 2000;86:e36–e41
  76. He J, Vupputuri S, Allen K, et al.  Passive smoking and the risk of coronary heart disease—a meta-analysis of epidemiologic studies. N Engl J Med. 1999;340:920–926
  77. Glantz SA, Parmley WW. Even a little second hand smoke is dangerous. JAMA. 2001;286:462–463
  78. Anonymous . Annual smoking attributable mortality, years of potential life lost and economic costs—United States 1995–1999. MMWR Morb Mortal Wkly Rep. 2002;51:300–303
  79. Sumida H, Watanabe H, Kugiyama K, et al.  Does passive smoking impair endothelium-dependent coronary artery dilation in women?. J Am Coll Cardiol. 1998;31:811–815
  80. Howard DJ, Ota RB, Briggs LA, et al.  Environmental tobacco smoke in the workplace induces oxidative stress in employees, including increased production of 8-hydroxy-2′-deoxyguanosine. Cancer Epidemiol Biomarkers Prev. 2002;7:141–146
  81. Visioli F, Galli C, Plasmati E, et al.  Olive phenol hydroxytyrosol prevents passive smoking-induced oxidative stress. Circulation. 2000;102:2169–2171
  82. Valkonen M, Kuusi T. Passive smoking induces atherogenic changes in low-density lipoprotein. Circulation. 2003;97:2012–2016
  83. Lifrak P, Gariti P, Alterman AI, et al.  Results of two levels of adjunctive treatment used with the nicotine patch. Am J Addict. 1997;6:93–98
  84. Joseph AM, Norman SM, Ferry LH, et al.  The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med. 1996;335:1792–1798
  85. Heeschen C, Jang JJ, Weis M, et al.  Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001;7:833–839
  86. Hill P, Haley NJ, Wynder EL. Cigarette smoking (Carboxyhemoglobin, plasma nicotine, cotinine and thiocyanate vs self-reported smoking data and cardiovascular disease). J Chronic Dis. 1983;36:439–449
  87. Heeschen C, Weis M, Aicher A, et al.  A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. J Clin Invest. 2002;110:527–536
  88. Aicher A, Heeschen C, Mohaupt M, et al.  Nicotine strongly activates dendritic cell-mediated adaptive immunity (Potential role for the progression of atherosclerotic lesions). Circulation. 2003;107:604–611
  89. Wei W, Kim Y, Boudreau N. Association of smoking with serum and dietary levels of antioxidants in adults (NHANES III, 1988-1994). Am J Public Health. 2001;91:258–264
  90. Ma J, Hampl JS, Betts NM. Antioxidant intakes and smoking status (Data from the continuing survey of food intakes by individuals 1994-1996). Am J Clin Nutr. 2000;71:774–780
  91. Walmsey CM, Bates CJ, Cole TJ. Relationship between cigarette smoking and nutrient intakes and blood status of older people living in the UK (Further analysis of data from the National Diet and Nutrition Survey of people aged 65 years and over, 1994/95). Public Health Nutr. 2003;2:199–208
  92. D’Avanzo B, La Vecchia C, Braga C, et al.  Nutrient intake according to education, smoking and alcohol in Italian women. Nutr Cancer. 1997;28:46–51
  93. Panda K, Chattopadhyay R, Ghosh MK, et al.  Vitamin C prevents cigarette smoke induced oxidative damage of proteins and increased proteolysis. Free Radic Biol Med. 1999;27:1064–1079
  94. Panda K, Chattopadhyay R, Chattopadhyay DJ, et al.  Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. Free Radic Biol Med. 2000;29:115–124
  95. Neunteufl T, Priglinger U, Heher S, et al.  Effects of vitamin E on chronic and acute endothelial dysfunction. J Am Coll Cardiol. 2000;35:277–283
  96. Mulholland CW, Strain JJ, Trinick TR. Serum antioxidant potential, and lipoprotein oxidation in female smokers following vitamin C supplementation. Int J Food Sci Nutr. 1996;47:227–231
  97. van Tits LJ, de Waart F, Hak-Lemmers HL, et al.  Effects of alpha-tocopherol on superoxide production and plasma intercellular adhesion molecule-1 and antibodies to oxidized LDL in chronic smokers. Free Radic Biol Med. 2001;30:1122–1129
  98. Habib MP, Tank LJ, Lane LC, et al.  Effect of vitamin E on exhaled ethane in cigarette smokers. Chest. 1999;11:684–690
  99. Jialal I, Devaraj S. Antioxidants and atherosclerosis (Don’t throw out the baby with the bath water). Circulation. 2003;107:926–928
  100. Meagher EA, Barry OP, Lawson JA, et al.  Effects of Vitamin E on lipid peroxidation in healthy volunteers. JAMA. 2001;285:1178–1182
  101. Patrignani P, Panara MR, Tacconelli S, et al.  Effects of vitamin E supplementation on F2-isoprostane and thromboxane biosynthesis in healthy cigarette smokers. Circulation. 2000;102:539–545
  102. Dietrich M, Block G, Hudes M, et al.  Antioxidant supplementation decreases lipid peroxidation biomarker F2-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev. 2002;11:7–13
  103. Heitzer T, Herttuala SY, Wild E, et al.  Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both. J Am Coll Cardiol. 1999;33:499–505
  104. Porkkala-Sarataho EK, Jukka T, Nyyssonen MK, et al.  Long-term effects of vitamin E, vitamin C, and combination supplementation on urinary 7-hydro-8-oxo-2′-deoxyguanosine, serum cholesterol oxidation products, and oxidation resistance of lipids in nondepleted men. Arterioscler Thromb Vasc Biol. 2000;20:2087–2093
  105. Traber MG, Winklhofer-Roob BM, Roob JM, et al.  Vitamin E kinetics in smokers and nonsmokers. Free Radic Biol Med. 2001;31:1368–1374
  106. Jacobson JS, Begg MD, Wang LW, et al.  Effects of a 6-month vitamin intervention of DNA damage in heavy smokers. Cancer Epidemiol Biomarkers Prev. 2000;9:1303–1311
  107. Fuller CJ, May MA, Martin KJ. The effect of vitamin E and vitamin C supplementation of LDL oxidisability and neutrophil respiratory burst in young smokers. J Am Coll Nutr. 2000;19:361–369
  108. Aghdassi E, Royall D, Allard JP. Oxidative stress in smokers supplemented with vitamin C. Int J Vitam Nutr Res. 1999;69:45–51
  109. Porkkala-Sarataho EK, Nyyssonen MK, Kaikkonen JE, et al.  A randomised, single-blind, placebo-controlled trial of the effects of 200mg alpha-tocopherol on the oxidation resistance of atherogenic lipoproteins. Am J Clin Nutr. 1998;68:1034–1041
  110. Rapola JM, Virtamo J, Ripatti S, et al.  Effects of alpha tocopherol and beta carotene supplements on symptoms, progression and prognosis of angina pectoris. Heart. 1998;79:454–458
  111. Teikari JM, Laatikainen L, Rapola JM, et al.  Retinal vascular changes following supplementation with alpha-tocopherol or beta-carotene. Acta Ophthalmol Scand. 1998;76:68–73
  112. Samman S, Brown AJ, Beltran C, et al.  The effect of ascorbic acid on plasma lipids and oxidisability of LDL in male smokers. Eur J Clin Nutr. 1997;51:472–477
  113. Rapola JM, Virtamo J, Ripatti S, et al.  Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarctions. Lancet. 1997;349:1715–1720
  114. Nyyssonen MK, Poulsen HE, Hayn EM, et al.  Effect of supplementation of smoking men with plain or slow release ascorbic acid on lipoprotein oxidation. Eur J Clin Nutr. 1997;51:154–163
  115. Prieme H, Loft S, Nyyssonen MK, et al.  No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on oxidative damage DNA damage estimated by 8-oxo-7,8-dihydro-2′-deoxyguanosine excretion in smokers. Am J Clin Nutr. 1997;65:503–507
  116. Porkkala-Sarataho EK, Nyyssonen MK, Salonen JT. Increased oxidation resistance of atherogenic plasma lipoproteins at high vitamin E levels in non-vitamin E supplemented men. Atherosclerosis. 1996;124:83–94
  117. Rapola JM, Virtamo J, Haukka JK, et al.  Effect of vitamin E and beta carotene on the incidence of angina pectoris (A randomised double-blind, controlled trial). JAMA. 1996;275:693–698
  118. Theron AJ, Anderson R. Investigation of the effects of oral administration of ascorbate on the functional activity of serum alpha-1-protease inhibitor and oxidant release by blood phagocytes from cigarette smokers in a placebo-controlled, double blind crossover trial. Int J Vitam Nutr Res. 1988;58:218–224

 Supported by grants (HL70128, HL-54500, HL-62250, HL61364, HL54500, and RR16293) from the National Institutes of Health. G.A.F. is the Robinette Foundation Professor of Cardiovascular Medicine and the Bobst Professor of Pharmacology.

PII: S0033-0620(03)00076-8

doi: 10.1016/S0033-0620(03)00076-8

Progress in Cardiovascular Diseases
Volume 46, Issue 1 , Pages 79-90 , July 2003