Statins as Pleiotropic Modifiers of Vascular Oxidative Stress and Inflammation

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world and in the future is expected to be the number one killer worldwide. The main cause underlying CVD is atherosclerosis. A key event in atherosclerosis initiation and progression is oxidative stress through the production of reactive oxygen species as well as endothelial dysfunction. Several pro- inflammatory and anti-inflammatory cytokines and proteins are involved in this process, complemented by activation of adhesion molecules that promote leukocyte rolling, tethering and infiltration into the sub-endothelial space. Statins represent the agent of choice since numerous clinical trials have verified that their pharmacological action extends beyond lipid lowering. Statins demonstrate direct anti-oxidant effects by scavenging free radicals and stimulating anti-oxidant enzymes while acting as regulators for cytokine, protein and adhesion molecule expression, all of which are involved in the atherosclerotic process. Statin use is considered one of the most efficient currently used interventions in managing CVD with the likely hood of remaining so in the near future.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Lee R, Margaritis M, Channon KM, et al. Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations. Curr Med Chem. 2012;19:2504-20.

  • 2. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins. J Am Coll Cardiol. 2014;63:2491-502.

  • 3. Psarros C, Lee R, Margaritis M, et al. Nanomedicine for the prevention, treatment and imaging of atherosclerosis. Nanomedicine. 2012;8 Suppl 1:S59-68.

  • 4. Antoniades C, Antonopoulos AS, Tousoulis D, et al. Adiponectin: from obesity to cardiovascular disease. Obes Rev. 2009;10:269-79.

  • 5. Antonopoulos AS, Lee R, Margaritis M, et al. Adiponectin as a regulator of vascular redox state: therapeutic implications. Recent Pat Cardiovasc Drug Discov. 2011;6:78-88.

  • 6. Margaritis M, Antonopoulos AS, Digby J, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013;127:2209-21.

  • 7. Antonopoulos AS, Margaritis M, Coutinho P, et al. Adiponectin As A Link Between Type 2 Diabetes Mellitus And Vascular NADPH-Oxidase Activity In The Human Arterial Wall: The Regulatory Role Of Perivascular Adipose Tissue. Diabetes. 2014. doi: 10.2337/db14-1011 [Epub ahead of print]

  • 8. Channon KM and Guzik TJ. Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol. 2002;53:515-24.

  • 9. Alp NJ, Mussa S, Khoo J, et al. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J Clin Invest. 2003;112:725-35.

  • 10. Cunnington C, Van Assche T, Shirodaria C, et al. Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease. Circulation. 2012;125:1356-66.

  • 11. Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109:II27-33.

  • 12. Antoniades C, Tousoulis D, Vasiliadou C, et al. Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction. J Am Coll Cardiol. 2005;46:1101-9.

  • 13. Antoniades C, Shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006;114:1193-201.

  • 14. Antoniades C, Shirodaria C, Leeson P, et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J. 2009;30:1142-50.

  • 15. Gounari P, Tousoulis D, Antoniades C, et al. Rosuvastatin but not ezetimibe improves endothelial function in patients with heart failure, by mechanisms independent of lipid lowering. Int J Cardiol. 2010;142:87-91.

  • 16. Antoniades C, Demosthenous M, Tousoulis D, et al. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis. Hypertension. 2011;58:93-8.

  • 17. Ait-Oufella H, Taleb S, Mallat Z, et al. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31:969-79.

  • 18. Tousoulis D, Antoniades C, Stefanadis C. Assessing inflammatory status in cardiovascular disease. Heart. 2007;93:1001-7.

  • 19. Kim JH, Bachmann RA, Chen J. Interleukin-6 and insulin resistance. Vitam Horm. 2009;80:613-33.

  • 20. Schuett H, Luchtefeld M, Grothusen C, et al. How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost. 2009;102:215-22.

  • 21. Abeywardena MY, Leifert WR, Warnes KE, et al. Cardiovascular biology of interleukin-6. Curr Pharm Des. 2009;15:1809-21.

  • 22. Yudkin JS, Kumari M, Humphries SE, et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis. 2000;148:209-14.

  • 23. Hartge MM, Unger T, Kintscher U. The endothelium and vascular inflammation in diabetes. Diab Vasc Dis Res. 2007;4:84-8.

  • 24. Wang Z, Castresana MR, Newman WH. Reactive oxygen and NFkappaB in VEGF-induced migration of human vascular smooth muscle cells. Biochem Biophys Res Commun. 2001;285:669-74.

  • 25. Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol. 2008;4:34-42.

  • 26. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479-90.

  • 27. Okamura H, Tsutsui H, Kashiwamura S, et al. Interleukin-18: a novel cytokine that augments both innate and acquired immunity. Adv Immunol. 1998;70:281-312.

  • 28. Pizarro TT, Cominelli F. Cloning IL-1 and the birth of a new era in cytokine biology. J Immunol. 2007;178:5411-2.

  • 29. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy--review of a new approach. Pharmacol Rev. 2003;55:241-69.

  • 30. Han X, Kitamoto S, Wang H, et al. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J. 2010;24:2869-80.

  • 31. Han X, Kitamoto S, Lian Q, et al. Interleukin-10 facilitates both cholesterol uptake and efflux in macrophages. J Biol Chem. 2009;284:32950-8.

  • 32. Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol. 2003;73:213-24.

  • 33. Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002;106:24-30.

  • 34. Tziakas DN, Chalikias GK, Kaski JC, et al. Inflammatory and anti-inflammatory variable clusters and risk prediction in acute coronary syndrome patients: a factor analysis approach. Atherosclerosis. 2007;193:196-203.

  • 35. Lin S, Lee CK, Wang YM, et al. Measurement of dimensions of pentagonal doughnut-shaped C-reactive protein using an atomic force microscope and a dual polarisation interferometric biosensor. Biosens Bioelectron. 2006;22:323-7.

  • 36. Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation. 2003;108:1930-2.

  • 37. Venugopal SK, Devaraj S, Jialal I. Macrophage conditioned medium induces the expression of C-reactive protein in human aortic endothelial cells: potential for paracrine/autocrine effects. Am J Pathol. 2005;166:1265-71.

  • 38. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805-12.

  • 39. Rifai N, Ridker PM. Proposed cardiovascular risk assessment algorithm using high-sensitivity C-reactive protein and lipid screening. Clin Chem. 2001;47:28-30.

  • 40. Elkind MS. Inflammation, atherosclerosis, and stroke. Neurologist. 2006;12:140-8.

  • 41. King VL, Thompson J, Tannock LR. Serum amyloid A in atherosclerosis. Curr Opin Lipidol. 2011;22:302-7.

  • 42. Rho YH, Chung CP, Oeser A, et al. Novel cardiovascular risk factors in premature coronary atherosclerosis associated with systemic lupus erythematosus. J Rheumatol. 2008;35:1789-94.

  • 43. Min JH, Jain MK, Wilder C, et al. Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry. 1999;38:12935-42.

  • 44. Wilensky RL and Macphee CH. Lipoprotein-associated phospholipase A(2) and atherosclerosis. Curr Opin Lipidol. 2009;20:415-20.

  • 45. Anderson JL. Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention. Am J Cardiol. 2008;101:23F-33F.

  • 46. Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003;170:191-203.

  • 47. McEver RP. Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol. 2002;14:581-6.

  • 48. Galkina E, Kadl A, Sanders J, et al. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med. 2006;203:1273-82.

  • 49. Eriksson EE, Xie X, Werr J, et al. Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med. 2001;194:205-18.

  • 50. Galkina E and Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27:2292-301.

  • 51. Paez A, Mendez-Cruz AR, Varela E, et al. HUVECs from newborns with a strong family history of myocardial infarction overexpress adhesion molecules and react abnormally to stimulating agents. Clin Exp Immunol. 2005;141:449-58.

  • 52. Davies MJ, Gordon JL, Gearing AJ, et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol. 1993;171:223-9.

  • 53. Yu G, Rux AH, Ma P, et al. Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-kappaB-dependent manner. Blood. 2005;105:3545-51.

  • 54. Hafezi-Moghadam A, Thomas KL, Prorock AJ, et al. L-selectin shedding regulates leukocyte recruitment. J Exp Med. 2001;193:863-72.

  • 55. del Pozo MA, Pulido R, Munoz C, et al. Regulation of ICAM-3 (CD50) membrane expression on human neutrophils through a proteolytic shedding mechanism. Eur J Immunol. 1994;24:2586-94.

  • 56. Kostidou E, Topouridou K, Daniilidis A, et al. Oxidized laminin-1 induces increased monocyte attachment and expression of ICAM-1 in endothelial cells. Int J Exp Pathol. 2009;90:630-7.

  • 57. Matheny HE, Deem TL, Cook-Mills JM. Lymphocyte migration through monolayers of endothelial cell lines involves VCAM-1 signaling via endothelial cell NADPH oxidase. J Immunol. 2000;164:6550-9.

  • 58. Malik I, Danesh J, Whincup P, et al. Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis. Lancet. 2001;358:971-6.

  • 59. Woodfin A, Voisin MB, Nourshargh S. PECAM-1: a multifunctional molecule in inflammation and vascular biology. Arterioscler Thromb Vasc Biol. 2007;27:2514-23.

  • 60. Wong CW, Wiedle G, Ballestrem C, et al. PECAM-1/CD31 transhomophilic binding at the intercellular junctions is independent of its cytoplasmic domain; evidence for heterophilic interaction with integrin alphavbeta3 in Cis. Mol Biol Cell. 2000;11:3109-21.

  • 61. Mandell KJ, Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev. 2005;57:857-67.

  • 62. Babinska A, Azari BM, Salifu MO, et al. The F11 receptor (F11R/JAM-A) in atherothrombosis: overexpression of F11R in atherosclerotic plaques. Thromb Haemost. 2007;97:272-81.

  • 63. Ostermann G, Fraemohs L, Baltus T, et al. Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium: inhibition by soluble JAM-A. Arterioscler Thromb Vasc Biol. 2005;25:729-35.

  • 64. Zernecke A, Liehn EA, Fraemohs L, et al. Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. Arterioscler Thromb Vasc Biol. 2006;26:e10-3.

  • 65. Keiper T, Al-Fakhri N, Chavakis E, et al. The role of junctional adhesion molecule-C (JAM-C) in oxidized LDL-mediated leukocyte recruitment. FASEB J. 2005;19:2078-80.

  • 66. Weitz-Schmidt G. Lymphocyte function-associated antigen-1 blockade by statins: molecular basis and biological relevance. Endothelium. 2003;10:43-7.

  • 67. Welzenbach K, Hommel U, Weitz-Schmidt G. Small molecule inhibitors induce conformational changes in the I domain and the I-like domain of lymphocyte function-associated antigen-1. Molecular insights into integrin inhibition. J Biol Chem. 2002;277:10590-8.

  • 68. Romano M, Mezzetti A, Marulli C, et al. Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: role of nitric oxide. J Investig Med. 2000;48:183-9.

  • 69. Seljeflot I, Tonstad S, Hjermann I, et al. Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease. Atherosclerosis. 2002;162:179-85.

  • 70. Rezaie-Majd A, Maca T, Bucek RA, et al. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002;22:1194-9.

  • 71. Izidoro-Toledo TC, Guimaraes DA, Belo VA, et al. Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells. Naunyn Schmiedebergs Arch Pharmacol. 2011;383:547-54.

  • 72. Franzoni F, Quinones-Galvan A, Regoli F, et al. A comparative study of the in vitro antioxidant activity of statins. Int J Cardiol. 2003;90:317-21.

  • 73. Davignon J, Jacob RF, Mason RP. The antioxidant effects of statins. Coron Artery Dis. 2004;15:251-8.

  • 74. Lim S, Barter P. Antioxidant effects of statins in the management of cardiometabolic disorders. J Atheroscler Thromb. 2014;21:997-1010.

  • 75. Antoniades C, Bakogiannis C, Tousoulis D, et al. Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation. 2010;122:S66-73.

  • 76. Antoniades C, Bakogiannis C, Leeson P, et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterinmediated endothelial nitric oxide synthase coupling. Circulation. 2011;124:335-45.

  • 77. Antonopoulos AS, Margaritis M, Shirodaria C, et al. Translating the effects of statins: from redox regulation to suppression of vascular wall inflammation. Thromb Haemost. 2012;108:840-8.

  • 78. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307-16.

  • 79. Officers A, Coordinators for the ACRGTA, Lipid-Lowering Treatment to Prevent Heart Attack T. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998-3007.

  • 80. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-58.

  • 81. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248-61.

  • 82. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

  • 83. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-207.

  • 84. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-57.

  • 85. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-7.

OPEN ACCESS

Journal + Issues

Search