Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: The role of statins

Antioxidants and Redox Signaling

Volumn 20, Issue 8, 2014, Pages 1216-1237

  Hermida, Nerea ^a   Balligand, Jean Luc ^a,b  

^a UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

^b CLINIQUES UNIVERSITAIRES SAINT LUC   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; ANTI-INFLAMMATORY AGENTS; ATHEROSCLEROSIS; CHOLESTEROL, LDL; ENDOTHELIAL CELLS; ENDOTHELIUM, VASCULAR; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; NITRIC OXIDE; NITRIC OXIDE SYNTHASE TYPE III; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 84894470406     PISSN: 15230864     EISSN: 15577716     Source Type: Journal    
DOI: 10.1089/ars.2013.5537     Document Type: Review

References (200)

1. Abe J and Berk BC. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc Med 8: 59-64, 1998.
2. Abe J, Takahashi M, Ishida M, Lee JD, and Berk BC. c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1. J Biol Chem 272: 20389-20394, 1997.
3. Abe M, Maruyama N, Okada K, Matsumoto S, Matsumoto K, and Soma M. Effects of lipid-lowering therapy with rosuvastatin on kidney function and oxidative stress in patients with diabetic nephropathy. J Atheroscler Thromb 18: 1018-1028, 2011.
4. Abetel G, Poget PN, and Bonnabry JP. [Hypotensive effect of an inhibitor of cholesterol synthesis (fluvastatin). A pilot study]. Schweiz Med Wochenschr[Article in French] 128: 272-277, 1998.
5. Adam O, Neuberger HR, Bohm M, and Laufs U. Prevention of atrial fibrillation with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Circulation 118: 1285-1293, 2008.
6. Amarenco P and Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 8: 453-463, 2009.
7. Angeloni E, Paneni F, Landmesser U, Benedetto U, Melina G, Luscher TF, et al. Lack of protective role of HDL-C in patients with coronary artery disease undergoing elective coronary artery bypass grafting. Eur Heart J 2013 [Epub ahead of print]; DOI: 10.1093/eurheartj/eht163.
8. Antoniades C, Bakogiannis C, Leeson P, Guzik TJ, Zhang MH, Tousoulis D, et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin- mediated endothelial nitric oxide synthase coupling. Circulation 124: 335-345, 2011.
9. Antoniades C, Tousoulis D, Vasiliadou C, Pitsavos C, Chrysochoou C, Panagiotakos D, 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 46: 1101-1109, 2005.
10. Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, and Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA 91: 7583-7587, 1994.
11. Balligand JL. Vitamin B or L-arginine supplementation in hyperhomocysteinaemia: think twice! Cardiovasc Res 96: 165-166, 2012.
12. Bassell G and Singer RH. mRNA and cytoskeletal filaments. Curr Opin Cell Biol 9: 109-115, 1997.
13. Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 121: 2693-2708, 2011.
14. Bist A, Fielding PE, and Fielding CJ. Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol. Proc Natl Acad Sci USA 94: 10693-10698, 1997.
15. Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98: 1842-1847, 1998.
16. Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, et al. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 87: 99-105, 2000.
17. Boger RH, Vallance P, and Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atheroscler Suppl 4: 1-3, 2003.
18. Borghi C, Prandin MG, Costa FV, Bacchelli S, Degli ED, and Ambrosioni E. Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia. J Cardiovasc Pharmacol 35: 549-555, 2000.
19. Burgoyne JR, Oka S, Ale-Agha N, and Eaton P. Hydrogen peroxide sensing and signaling by protein kinases in the cardiovascular system. Antioxid Redox Signal 18: 1042-1052, 2013.
20. Cai H, Li Z, Dikalov S, Holland SM, Hwang J, Jo H, et al. NAD(P)H oxidase-derived hydrogen peroxide mediates endothelial nitric oxide production in response to angiotensin II. J Biol Chem 277: 48311-48317, 2002.
21. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350: 1495-1504, 2004.
22. Castro PF, Miranda R, Verdejo HE, Greig D, Gabrielli LA, Alcaino H, et al. Pleiotropic effects of atorvastatin in heart failure: role in oxidative stress, inflammation, endothelial function, and exercise capacity. J Heart Lung Transplant 27: 435-441, 2008.
23. Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol 30: 325-333, 1997.
24. Channon KM. Oxidative stress and coronary plaque stability. Arterioscler Thromb Vasc Biol 22: 1751-1752, 2002.
25. Chen CA, Wang TY, Varadharaj S, Reyes LA, Hemann C, Talukder MA, et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468: 1115-1118, 2010.
26. Chen MS, Xu FP, Wang YZ, Zhang GP, Yi Q, Zhang HQ, et al. Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis. J Mol Cell Cardiol 37: 889-896, 2004.
27. Chen W, Bacanamwo M, and Harrison DG. Activation of p300 histone acetyltransferase activity is an early endothelial response to laminar shear stress and is essential for stimulation of endothelial nitric-oxide synthase mRNA transcription. J Biol Chem 283: 16293-16298, 2008.
28. Chen Z, Peng IC, Sun W, Su MI, Hsu PH, Fu Y, et al. AMPactivated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res 104: 496-505, 2009.
29. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, et al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 443: 285-289, 1999.
30. Choi SH, Chae A, Miller E, Messig M, Ntanios F, DeMaria AN, et al. Relationship between biomarkers of oxidized lowdensity lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol 52: 24-32, 2008.
31. Cleland JG, McMurray JJ, Kjekshus J, Cornel JH, Dunselman P, Fonseca C, et al. Plasma concentration of aminoterminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure). J Am Coll Cardiol 54: 1850-1859, 2009.
32. Coffer PJ, Jin J, and Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335 (Pt 1): 1-13, 1998.
33. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3: 403-416, 2006.
34. Corson MA, James NL, Latta SE, Nerem RM, Berk BC, and Harrison DG. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res 79: 984-991, 1996.
35. Cudmore M, Ahmad S, Al-Ani B, Fujisawa T, Coxall H, Chudasama K, et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 115: 1789-1797, 2007.
36. De CR, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Jr., et al. Nitric oxide decreases cytokineinduced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96: 60-68, 1995.
37. De GC, V, Bianchi M, Pascale V, Ferrario P, Morelli F, Pascale W, et al. Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide synthase and a novel cardiovascular risk molecule. Med Sci Monit 15: RA91-RA101, 2009.
38. Deanfield JE, Halcox JP, and Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 115: 1285-1295, 2007.
39. Desjardins F, Lobysheva I, Pelat M, Gallez B, Feron O, Dessy C, et al. Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis. Cardiovasc Res 79: 527-536, 2008.
40. Desjardins F, Sekkali B, Verreth W, Pelat M, De KD, Mertens A, et al. Rosuvastatin increases vascular endothelial PPARgamma expression and corrects blood pressure variability in obese dyslipidaemic mice. Eur Heart J 29: 128-137, 2008.
41. Diers AR, Broniowska KA, Darley-Usmar VM, and Hogg N. Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells. Am J Physiol Heart Circ Physiol 301: H803-H812, 2011.
42. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, and Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399: 601-605, 1999.
43. Dong M, Yan BP, Liao JK, Lam YY, Yip GW, and Yu CM. Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today 15: 622-629, 2010.
44. Doshi AA, Ziolo MT, Wang H, Burke E, Lesinski A, and Binkley P. A promoter polymorphism of the endothelial nitric oxide synthase gene is associated with reduced mRNA and protein expression in failing human myocardium. J Card Fail 16: 314-319, 2010.
45. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10: 262-267, 1998.
46. Drexler H. Endothelial dysfunction: clinical implications. Prog Cardiovasc Dis 39: 287-324, 1997.
47. Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 104: 342-345, 2001.
48. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205: 2409-2417, 2008.
49. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 95: 8880-8885, 1998.
50. Feron O, Dessy C, Desager JP, and Balligand JL. Hydroxymethylglutaryl- coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation 103: 113-118, 2001.
51. Feron O, Dessy C, Moniotte S, Desager JP, and Balligand JL. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 103: 897-905, 1999.
52. Fish JE and Marsden PA. Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium. Cell Mol Life Sci 63: 144-162, 2006.
53. Fish JE, Yan MS, Matouk CC, St BR, Ho JJ, Gavryushova A, et al. Hypoxic repression of endothelial nitric-oxide synthase transcription is coupled with eviction of promoter histones. J Biol Chem 285: 810-826, 2010.
54. Fisslthaler B and Fleming I. Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res 105: 114-127, 2009.
55. Forstermann U and Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113: 1708-1714, 2006.
56. Fukuta H and Little WC. Observational studies of statins in heart failure with preserved systolic function. Heart Fail Clin 4: 209-216, 2008.
57. Fulton D, Church JE, Ruan L, Li C, Sood SG, Kemp BE, et al. Src kinase activates endothelial nitric-oxide synthase by phosphorylating Tyr-83. J Biol Chem 280: 35943-35952, 2005.
58. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399: 597-601, 1999.
59. Furchgott RF and Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373-376, 1980.
60. Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, and Krayenbuehl HP. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 73: 865-876, 1986.
61. Ghosh S and Karin M. Missing pieces in the NF-kappaB puzzle. Cell 109 Suppl: S81-S96, 2002.
62. Gimbrone MA, Jr. Endothelial dysfunction, hemodynamic forces, and atherosclerosis. Thromb Haemost 82: 722-726, 1999.
63. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 113: e873-e923, 2006.
64. Gomez-Garre D, Gonzalez-Rubio ML, Munoz-Pacheco P, Caro-Vadillo A, Aragoncillo P, and Fernandez-Cruz A. Rosuvastatin added to standard heart failure therapy improves cardiac remodelling in heart failure rats with preserved ejection fraction. Eur J Heart Fail 12: 903-912, 2010.
65. Gonzalez-Sanchez JL, Martinez-Larrad MT, Saez ME, Zabena C, Martinez-Calatrava MJ, and Serrano-Rios M. Endothelial nitric oxide synthase haplotypes are associated with features of metabolic syndrome. Clin Chem 53: 91-97, 2007.
66. Govers R and Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 280: F193-F206, 2001.
67. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 204: 2449-2460, 2007.
68. Haghikia A, Missol-Kolka E, Tsikas D, Venturini L, Brundiers S, Castoldi M, et al. Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes. Eur Heart J 32: 1287-1297, 2011.
69. Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen NQ, Scherr M, et al. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest 123: 2143-2154, 2013.
70. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 100: 2153-2157, 1997.
71. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, et al. Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation 109: 2234-2239, 2004.
72. Hattori Y, Nakanishi N, and Kasai K. Statin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells. Cardiovasc Res 54: 649-658, 2002.
73. Haudek SB, Gupta D, Dewald O, Schwartz RJ, Wei L, Trial J, et al. Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation. Cardiovasc Res 83: 511-518, 2009.
74. Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, and White HD. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 105: 1446-1452, 2002.
75. Heinecke JW. Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis. Atherosclerosis 141: 1-15, 1998.
76. Hergenreider E, Heydt S, Treguer K, Boettger T, Horrevoets AJ, Zeiher AM, et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14: 249-256, 2012.
77. Hermida N, Markl A, Hamelet J, Van AT, Vanderper A, Herijgers P, et al. HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome. Cardiovasc Res 99: 44-54, 2013.
78. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 101: 2711-2719, 1998.
79. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, et al. A common variant of the endothelial nitric oxide synthase (Glu298/Asp) is a major risk factor for coronary artery disease in the UK. Circulation 100: 1515-1520, 1999.
80. Honjo T, Inoue N, Shiraki R, Kobayashi S, Otsui K, Takahashi M, et al. Endothelial urocortin has potent antioxidative properties and is upregulated by inflammatory cytokines and pitavastatin. J Vasc Res 43: 131-138, 2006.
81. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377: 239-242, 1995.
82. Huikuri HV, Jokinen V, Syvanne M, Nieminen MS, Airaksinen KE, Ikaheimo MJ, et al. Heart rate variability and progression of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 19: 1979-1985, 1999.
83. Imamura A, Takahashi R, Murakami R, Kataoka H, Cheng XW, Numaguchi Y, et al. The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels. Eur J Endocrinol 158: 189-195, 2008.
84. Indolfi C, Cioppa A, Stabile E, Di LE, Esposito G, Pisani A, et al. Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol 35: 214-221, 2000.
85. Indolfi C, Di LE, Perrino C, Stingone AM, Curcio A, Torella D, et al. Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation 106: 2118-2124, 2002.
86. Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, et al. Mitogenic signaling mediated by oxidants in Rastransformed fibroblasts. Science 275: 1649-1652, 1997.
87. Istvan ES and Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292: 1160-1164, 2001.
88. Jacobs M, Plane F, and Bruckdorfer KR. Native and oxidized low-density lipoproteins have different inhibitory effects on endothelium-derived relaxing factor in the rabbit aorta. Br J Pharmacol 100: 21-26, 1990.
89. Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 357: 2248-2261, 2007.
90. Kleemann R, Princen HM, Emeis JJ, Jukema JW, Fontijn RD, Horrevoets AJ, et al. Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin. Circulation 108: 1368-1374, 2003.
91. Kok SH, Lin LD, Hou KL, Hong CY, Chang CC, Hsiao M, et al. Simvastatin inhibits cysteine-rich protein 61 expression in rheumatoid arthritis synovial fibroblasts through the regulation of sirtuin-1/FoxO3a signaling. Arthritis Rheum 65: 639-649, 2013.
92. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6: 1004-1010, 2000.
93. Ky B, Burke A, Tsimikas S, Wolfe ML, Tadesse MG, Szapary PO, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 51: 1653-1662, 2008.
94. Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 111: 2356-2363, 2005.
95. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111: 1201-1209, 2003.
96. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 110: 1933-1939, 2004.
97. Landmesser U, Hornig B, and Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation 109: II27-II33, 2004.
98. LaRosa JC, Deedwania PC, Shepherd J, Wenger NK, Greten H, DeMicco DA, et al. Comparison of 80 versus 10mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial). Am J Cardiol 105: 283-287, 2010.
99. Laufs U, Endres M, Stagliano N, Amin-Hanjani S, Chui DS, Yang SX, et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest 106: 15-24, 2000.
100. Laufs U, La F, V, Plutzky J, and Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97: 1129-1135, 1998.
101. Laufs U and Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273: 24266-24271, 1998.
102. Laufs U, Wassmann S, Hilgers S, Ribaudo N, Bohm M, and Nickenig G. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men. Am J Cardiol 88: 1306-1307, 2001.
103. Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol 14: 421-430, 2003.
104. Levin ER. Endothelins. N Engl J Med 333: 356-363, 1995.
105. Li D, Mehta JL. Antisense to LOX-1 inhibits oxidized LDLmediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation 101: 2889-2895, 2000.
106. Liao JK and Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45: 89-118, 2005.
107. Liao JK, Shin WS, Lee WY, and Clark SL. Oxidized lowdensity lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 270: 319-324, 1995.
108. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106: 987-992, 2002.
109. Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, Abbate A, Vrtovec B, Khan BV, et al. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol 104: 1708-1716, 2009.
110. Liu PY, Liu YW, Lin LJ, Chen JH, and Liao JK. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 119: 131-138, 2009.
111. Lobysheva I, Rath G, Sekkali B, Bouzin C, Feron O, Gallez B, et al. Moderate caveolin-1 downregulation prevents NADPH oxidase-dependent endothelial nitric oxide synthase uncoupling by angiotensin II in endothelial cells. Arterioscler Thromb Vasc Biol 31: 2098-2105, 2011.
112. Maack C, Kartes T, Kilter H, Schafers HJ, Nickenig G, Bohm M, et al. Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation 108: 1567-1574, 2003.
113. Maejima Y, Nobori K, Ono Y, Adachi S, Suzuki J, Hirao K, et al. Synergistic effect of combined HMG-CoA reductase inhibitor and angiotensin-II receptor blocker therapy in patients with chronic heart failure: the HF-COSTAR trial. Circ J 75: 589-595, 2011.
114. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, et al. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 92: 1866-1874, 1993.
115. Massaro M, Zampolli A, Scoditti E, Carluccio MA, Storelli C, Distante A, et al. Statins inhibit cyclooxygenase-2 and matrix metalloproteinase-9 in human endothelial cells: antiangiogenic actions possibly contributing to plaque stability. Cardiovasc Res 86: 311-320, 2010.
116. McTaggart F, Buckett L,Davidson R,Holdgate G,McCormick A, Schneck D, et al. Preclinical and clinical pharmacology of Rosuvastatin, a new3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitor. Am J Cardiol 87: 28B-32B, 2001.
117. Michel JB, Feron O, Sase K, Prabhakar P, and Michel T. Caveolin versus calmodulin. Counterbalancing allosteric modulators of endothelial nitric oxide synthase. J Biol Chem 272: 25907-25912, 1997.
118. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, and Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 52: 1769-1781, 2008.
119. Moncada S and Erusalimsky JD. Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol 3: 214-220, 2002.
120. Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, et al. Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 52: 1270-1275, 2003.
121. Munzel T, Sinning C, Post F, Warnholtz A, and Schulz E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med 40: 180-196, 2008.
122. Nabel EG, Selwyn AP, and Ganz P. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation 81: 850-859, 1990.
123. Negi S, Shukrullah I, Veledar E, Bloom HL, Jones DP, and Dudley SC. Statin therapy for the prevention of atrial fibrillation trial (SToP AF trial). J Cardiovasc Electrophysiol 22: 414-419, 2011.
124. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352: 29-38, 2005.
125. Node K, Fujita M, Kitakaze M, Hori M, and Liao JK. Shortterm statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 108: 839-843, 2003.
126. O'Driscoll G, Green D, and Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 95: 1126-1131, 1997.
127. Ohara Y, Peterson TE, Sayegh HS, Subramanian RR, Wilcox JN, and Harrison DG. Dietary correction of hypercholesterolemia in the rabbit normalizes endothelial superoxide anion production. Circulation 92: 898-903, 1995.
128. Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N, et al. Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 102: 2061-2071, 1998.
129. Ohtoshi K, Yamasaki Y, Gorogawa S, Hayaishi-Okano R, Node K, Matsuhisa M, et al. Association of (-)786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance. Diabetologia 45: 1594-1601, 2002.
130. Paneni F, Mocharla P, Akhmedov A, Costantino S, Osto E, Volpe M, et al. Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes. Circ Res 111: 278-289, 2012.
131. Panza JA, Casino PR, Kilcoyne CM, and Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 87: 1468-1474, 1993.
132. Paradossi U, Ciofini E, Clerico A, Botto N, Biagini A, and Colombo MG. Endothelial function and carotid intimamedia thickness in young healthy subjects among endothelial nitric oxide synthase Glu298/Asp and T-786/C polymorphisms. Stroke 35: 1305-1309, 2004.
133. Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 49: 1272-1278, 2007.
134. Pedersen TR, Cater NB, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, et al. Comparison of atorvastatin 80mg/day versus simvastatin 20 to 40 mg/day on frequency of cardiovascular events late (five years) after acute myocardial infarction (from the Incremental Decrease in End Points through Aggressive Lipid Lowering [IDEAL] trial). Am J Cardiol 106: 354-359, 2010.
135. Pehlivanidis AN, Athyros VG, Demitriadis DS, Papageorgiou AA, Bouloukos VJ, and Kontopoulos AG. Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease. Atherosclerosis 157: 463-469, 2001.
136. Pelat M, Dessy C, Massion P, Desager JP, Feron O, and Balligand JL. Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/-mice in vivo. Circulation 107: 2480-2486, 2003.
137. Pendyala S, Gorshkova IA, Usatyuk PV, He D, Pennathur A, Lambeth JD, et al. Role of Nox4 and Nox2 in hyperoxiainduced reactive oxygen species generation and migration of human lung endothelial cells. Antioxid Redox Signal 11: 747-764, 2009.
138. Phillips SA, Hatoum OA, and Gutterman DD. The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD. Am J Physiol Heart Circ Physiol 292: H93-H100, 2007.
139. Quyyumi AA, Dakak N, Mulcahy D, Andrews NP, Husain S, Panza JA, et al. Nitric oxide activity in the atherosclerotic human coronary circulation. J Am Coll Cardiol 29: 308-317, 1997.
140. Radomski MW, Palmer RM, and Moncada S. Modulation of platelet aggregation by an L-arginine-nitric oxide pathway. Trends Pharmacol Sci 12: 87-88, 1991.
141. Ramet ME, Ramet M, Lu Q, Nickerson M, Savolainen MJ, Malzone A, et al. High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life. J Am Coll Cardiol 41: 2288-2297, 2003.
142. Reddy KG, Nair RN, Sheehan HM, and Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 23: 833-843, 1994.
143. Rees DD, Palmer RM, Hodson HF, and Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol 96: 418-424, 1989.
144. Reilly SN, Jayaram R, Nahar K, Antoniades C, Verheule S, Channon KM, et al. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation 124: 1107-1117, 2011.
145. Riahi S, Christensen JH, Toft E, Skou HA, and Schmidt EB. HMG-CoA reductase inhibitors improve heart rate variability in patients with a previous myocardial infarction. Pharmacol Res 45: 479-483, 2002.
146. Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano T, et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke 36: 2251-2257, 2005.
147. Riwanto M, Rohrer L, Roschitzki B, Besler C, Mocharla P, Mueller M, et al. Altered activation of endothelial anti-and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation 127: 891-904, 2013.
148. Rodrigues AC. Efflux and uptake transporters as determinants of statin response. Expert Opin Drug Metab Toxicol 6: 621-632, 2010.
149. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 340: 115-126, 1999.
150. Rossi GP, Taddei S, Virdis A, Cavallin M, Ghiadoni L, Favilla S, et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 41: 938-945, 2003.
151. Rossig L, Li H, Fisslthaler B, Urbich C, Fleming I, Forstermann U, et al. Inhibitors of histone deacetylation downregulate the expression of endothelial nitric oxide synthase and compromise endothelial cell function in vasorelaxation and angiogenesis. Circ Res 91: 837-844, 2002.
152. Roy D, Perreault M, and Marette A. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. Am J Physiol 274: E692-E699, 1998.
153. Scalia R, Gooszen ME, Jones SP, Hoffmeyer M, Rimmer DM, III, Trocha SD, et al. Simvastatin exerts both antiinflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 103: 2598-2603, 2001.
154. Schwartz IF, Ayalon R, Chernichovski T, Reshef R, Chernin G, Weinstein T, et al. Arginine uptake is attenuated through modulation of cationic amino-acid transporter-1, in uremic rats. Kidney Int 69: 298-303, 2006.
155. Schwarz P, Diem R, Dun NJ, and Forstermann U. Endogenous and exogenous nitric oxide inhibits norepinephrine release from rat heart sympathetic nerves. Circ Res 77: 841-848, 1995.
156. Searles CD, Ide L, Davis ME, Cai H, and Weber M. Actin cytoskeleton organization and posttranscriptional regulation of endothelial nitric oxide synthase during cell growth. Circ Res 95: 488-495, 2004.
157. Shah PK, Kaul S, Nilsson J, and Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part I. Circulation 104: 2376-2383, 2001.
158. Simionescu M. Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler Thromb Vasc Biol 27: 266-274, 2007.
159. Simionescu M. Cellular dysfunction in inflammatory-related vascular disorders' review series. The inflammatory process: a new dimension of a 19 century old story. J Cell Mol Med 13: 4291-4292, 2009.
160. Singh N, Tamariz J, Chamorro G, and Medina-Franco JL. Inhibitors of HMG-CoA reductase: current and future prospects. Mini Rev Med Chem 9: 1272-1283, 2009.
161. Smith SC, Jr., Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 113: 2363-2372, 2006.
162. Somlyo AP and Somlyo AV. Ca2 + sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 83: 1325-1358, 2003.
163. Stalker TJ, Lefer AM, and Scalia R. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid. Br J Pharmacol 133: 406-412, 2001.
164. Stamler JS, Lamas S, and Fang FC. Nitrosylation. the prototypic redox-based signaling mechanism. Cell 106: 675-683, 2001.
165. Stauss HM, Nafz B, Mrowka R, and Persson PB. Blood pressure control in eNOS knock-out mice: comparison with other species under NO blockade. Acta Physiol Scand 168: 155-160, 2000.
166. Stauss HM and Persson PB. Role of nitric oxide in buffering short-term blood pressure fluctuations. News Physiol Sci 15: 229-233, 2000.
167. Su SF, Hsiao CL, Chu CW, Lee BC, and Lee TM. Effects of pravastatin on left ventricular mass in patients with hyperlipidemia and essential hypertension. Am J Cardiol 86: 514-518, 2000.
168. Sun HX, Zeng DY, Li RT, Pang RP, Yang H, Hu YL, et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 60: 1407-1414, 2012.
169. Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y, et al. Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation 114: 2655-2662, 2006.
170. Sundaresan M, Yu ZX, Ferrans VJ, Irani K, and Finkel T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270: 296-299, 1995.
171. Sydow K and Munzel T. ADMA and oxidative stress. Atheroscler Suppl 4: 41-51, 2003.
172. Takeda M, Yamashita T, Shinohara M, Sasaki N, Takaya T, Nakajima K, et al. Plasma tetrahydrobiopterin/dihydrobiopterin ratio: a possible marker of endothelial dysfunction. Circ J 73: 955-962, 2009.
173. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 108: 1429-1437, 2001.
174. Takemoto M, Sun J, Hiroki J, Shimokawa H, and Liao JK. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 106: 57-62, 2002.
175. Tanus-Santos JE, Desai M, and Flockhart DA. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 11: 719-725, 2001.
176. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 372: 1231-1239, 2008.
177. Thomas M and Mann J. Increased thrombotic vascular events after change of statin. Lancet 352: 1830-1831, 1998.
178. Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, et al. Beneficial effects of cholesterollowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 332: 481-487, 1995.
179. Valko M, Rhodes CJ, Moncol J, Izakovic M, and Mazur M. Free radicals, metals and antioxidants in oxidative stressinduced cancer. Chem Biol Interact 160: 1-40, 2006.
180. Vallance P and Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 24: 1023-1030, 2004.
181. Van AL and D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev 11: 2295-2322, 1997.
182. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95: 9220-9225, 1998.
183. Vecchione C and Brandes RP. Withdrawal of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors elicits oxidative stress and induces endothelial dysfunction in mice. Circ Res 91: 173-179, 2002.
184. Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, et al. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of L-arginine availability. Circulation 101: 1261-1266, 2000.
185. Vladimirova-Kitova LG. Asymmetric dimethylarginine-mechanisms and targets for therapeutic management. Folia Med (Plovdiv) 50: 12-21, 2008.
186. von EA and Rohrer L. Transendothelial lipoprotein transport and regulation of endothelial permeability and integrity by lipoproteins. Curr Opin Lipidol 20: 197-205, 2009.
187. Vyas AK, Guo H, Moss AJ, Olshansky B, McNitt SA, Hall WJ, et al. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol 47: 769-773, 2006.
188. Wang HD, Pagano PJ, Du Y, Cayatte AJ, Quinn MT, Brecher P, et al. Superoxide anion from the adventitia of the rat thoracic aorta inactivates nitric oxide. Circ Res 82: 810-818, 1998.
189. Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37: 1450-1457, 2001.
190. Wassmann S, Laufs U, Baumer AT, Muller K, Konkol C, Sauer H, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 59: 646-654, 2001.
191. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7: 687-692, 2001.
192. Weseler AR and Bast A. Oxidative stress and vascular function: implications for pharmacologic treatments. Curr Hypertens Rep 12: 154-161, 2010.
193. Wever RM, Luscher TF, Cosentino F, and Rabelink TJ. Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 97: 108-112, 1998.
194. Williams JK, Sukhova GK, Herrington DM, and Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 31: 684-691, 1998.
195. Yamakuchi M, Greer JJ, Cameron SJ, Matsushita K, Morrell CN, Talbot-Fox K, et al. HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. Circ Res 96: 1185-1192, 2005.
196. Yamamoto C, Fukuda N, Jumabay M, Saito K, Matsumoto T, Ueno T, et al. Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading. Hypertens Res 34: 348-353, 2011.
197. Yoshimura T, Hisatomi A, Kajihara S, Yasutake T, Ogawa Y, Mizuta T, et al. The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease. J Atheroscler Thromb 10: 43-47, 2003.
198. Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, et al. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med 7: 853-857, 2001.
199. Zeiher AM, Fisslthaler B, Schray-Utz B, and Busse R. Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res 76: 980-986, 1995.
200. Zhang MX, Ou H, Shen YH, Wang J, Wang J, Coselli J, et al. Regulation of endothelial nitric oxide synthase by small RNA. Proc Natl Acad Sci USA 102: 16967-16972, 2005.