Endothelial dysfunction is an early event in atherosclerosis and could be considered a response to the injury induced by major risk factors. There is evidence that endothelial dysfunction is intimately involved in the onset and the progression of cardiovascular disease through abnormalities in the production, release or degradation of endothelium-derived factors, mainly nitric oxide and endothelin 1. Several reports have shown that drugs of the statin class could have multiple beneficial effects related to endothelium-mediated vasoactive, antithrombotic, antiproliferative and anti-inflammatory actions. Thus, the question arises of whether endothelial cells are the main target of statin therapy, in the setting of both hypercholesterolemia and normocholesterolemia. Experimental and clinical studies are reported that could support this hypothesis.

Vaughan CJ, Gotto AM, Basson CT: The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000;35:1–10.
Maron DJ, Fazio S, Linton MRF: Current perspectives on statins. Circulation 2000;101:207–213.
Vaughan CJ, Murphy MB, Buckley BB: Statins do more than just lower cholesterol. Lancet 1996;348:1079–1082.
Waters D: Cholesterol lowering: Should it continue to be the last thing we do? Circulation 1999;99:3215–3217.
Jackson G: Statins and coronary artery disease: It’s the clinical endpoints that count. Br J Clin Pract 1997;51:2–3.
Vogel RA: Cholesterol lowering and endothelial function. Am J Med 1999;197:479–487.
Davignon J, Laaksonen R: Low-density lipoprotein-independent effects of statins. Curr Opin Lipidol 1999;10:543–559.
Visseren FL, Lansberg PJ, Erkelens DW, Kastelein JJ: Statins: Possibly more than just lowering of the lipid level. Ned Tijdschr Geneeskd 2000;144:316–321.
Ross R: Atherosclerosis – An inflammatory disease. N Engl J Med 1999;340:115–126.
Stroes ES, Koomans HA, de Bruin TW, Rabelink TJ: Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 1995;346:467–471.
Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA: Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567–574.
Panza JA, Garcia CE, Kilcoyne CM, Quyyumi AA, Cannon RO: Impaired endothelium-dependent vasodilation in patients with essential hypertension: Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation 1995;91:1732–1738.
Heitzer T, Yla Herttuala S, Luoma J, Kurz S, Munzel T, Just H, Olschewski M, Drexler H: Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia: Role of oxidized LDL. Circulation 1996;93:1346–1353.
Puddu P: Homocysteine and risk for atherothrombotic events. Cardiologia 1999;44:627–631.
Puddu P, Puddu GM, Zacà F, Muscari A: Endothelial dysfunction in hypertension. Acta Cardiol 2000;55:221–232.
Jessup W: Oxidized lipoproteins and nitric oxide. Curr Opin Lipidol 1996;7:274–280.
Ohara Y, Peterson TE, Harrison DG: Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993;91:2546–2551.
Wever RMF, Luscher TF, Cosentino F, Rabelink TJ: Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 1998;97:108–112.
Molinau H, Meinertz T, Hink U, Muenzel T: HMG-CoA reductase inhibition inhibits vascular NADH oxidase activity, prevents uncoupling of nitric oxide synthase and improves endothelial dysfunction in cholesterol fed rabbits (abstract). Eur Heart H 2000;21:16.
Williams JK, Sukhova GK, Herrington DM, Libby P: Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998;31:684–691.
Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW: Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. J Am Coll Cardiol 1999;33:234–241.
Laufs U, Fata VL, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–1135.
Feron OJ, Desager JP, Balligand JL: HMG CoA reductase inhibtion promotes NO production by decreasing abundance and the inhibitory interaction of caveolin with the endothelial nitric oxide synthase (abstract). Circulation 1999;100:I-336.
Walter DH, Schachinger V, Elsner M: Statin therapy counteracts the deleterious effects of increased oxidative stress on atherosclerotic disease progression (abstract). Circulation 1999;100:I-647.
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y: A novel potent vaosconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–415.
Flowers MA, Wang Y, Stewart RJ, Patel B, Marsden PA: Reciprocal regulation of endothelin-1 and endothelial constitutive NOS in proliferating endothelial cells. Am J Physiol 1995;269:H1988–H1997.
Ziesche R, Petkov V, Williams J, Zakeri SM, Mosgoller W, Knofler M, Vlock LH: Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue. Proc Natl Acad Sci USA 1996;93:12478–12483.
Lamas S, Michel T, Collins T, Brenner BM, Marsden PA: Effects of interferon-γ on nitric oxide synthase activity and endothelin-1 production by vascular endothelial cells. J Clin Invest 1992;90:879–887.
Mathew V, Cannan CR, Miller VM, Barber DA, Hasdai D, Schwartz RS, Holmes DR, Lerman A: Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental hypercholesterolemia. Circulation 1997;96:1930–1936.
Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau V: Impaired vasodilation of forearm vessels in hypercholesterolemic humans. J Clin Invest 1990;86:228–234.
Zeiher AM, Drexler H, Wollschager H, Just H: Modulation of vasomotor tone in humans: Progressive endothelial dysfunction with different early stages of atherosclerosis. Circulation 1991;83:391–401.
Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S: 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 1998;101:2711–2719.
Grantham JA, Rajamannan NM, Burnett JC Jr: HMG CoA reductase inhibition attenuates vascular endothelin-1 generation in experimental atherosclerosis (abstract). Circulation 1999;100:I–622.
Qiu S, Theroux P, Marcil M, Solymoss BC: Plasma endothelin-1 levels in stable and unstable angina. Cardiology 1993;82:12–19.
Dupuis J, Tardif JC, Cernacek P, Théroux P: Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes: The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) Trial. Circulation 1999;99:3227–3233.
Glorioso N, Troffa C, Filigheddu Fdettori F, Soro A, Pinna Parpaglia P, Collatina S, Pahor M: Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension 1999;34:1281–1286.
Palkama T: Induction of interleukin-1 production by ligands binding to the scavenger receptor in human monocytes and the THP-1 cell line. Immunology 1991;74:432–438.
Reaven PD, Khouw A, Beltz WF, Parthasarathy S, Witztum JL: Effect of dietary antioxidant combinations in humans: Protection of LDL by vitamin E but not by betacarotene. Arterioscler Thromb 1993;13:590–600.
Hoffman R, Brook GJ, Aviram M: Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: In vitro and ex vivo studies. Atherosclerosis 1992;93:105–113.
Aviram M, Dankner G, Cogan U: Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophages: In vitro and in vivo studies. Metabolism 1992;41:229–235.
Brosche T, Kral C, Summa JD, Platt D: Effective lovastatin therapy in elderly hypercholesterolemic patients – An antioxidative impact? Arch Gerontol Geriatr 1996;22:207–221.
Ghirlanda G, Oradei A, Manto A: Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: A double-blind, placebo-controlled study. J Clin Pharmacol 1993;33:226–229.
Watts GF, Castelluccio C, Rice-Evans C: Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 1993;46:1055–1057.
Giroux LM, Davignon J, Naruszewicz M: Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta 1993;1165:335–338.
Laaksonen R, Jokelainen K, Laakso J: The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 1996;77:851–854.
Mason RP: Direct antioxidant effects of atorvastatin and an active metabolite: A comparative analysis (abstract). Circulation 1999;100:I-541.
Scalia R, Lefer DJ, Lefer AM: Simvastatin inhibits leukocyte-endothelium interaction in vivo under normocholesterolemic conditions: Essential role of endothelial nitric oxide synthase (abstract). Circulation 1999;100:I-409.
Bellosta S, Bernini F, Ferri N: Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis 1998;137(suppl S):101–109.
Kimura M, Kurose I, Russell J, Granger DN: Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats. Arterioscler Thromb Vasc Biol 1997;17:1521–1526.
Holm T, Andreassen AK, Ueland T, Kjekshus E, Simonsen S, Aukrust P, Gullestad L: Pravastatin reduces soluble markers of inflammation and improves peripheral endothelial function in heart transplant recipients (abstract). Eur Heart J 2000;21:89.
Parissis J, Korovesis S, Kalivas P, Giagitzoglou E, Katritsis D: Short-term atorvastatin therapy reduces monocyte-related inflammatory markers in the serum of hypercholesterolaemic patients (abstract). Eur Heart J 2000;21:154.
Chase AJ, Newby AC: Cerivastatin inhibits metalloproteinase production by human vascular smooth muscle cells in response to inflammatory stimuli, a possible mechanism for plaque stabilisation (abstract). Eur Heart J 2000;21:152.
Sinkiewicz W, Hoffman A, Blazejewski J, Bujak R, Budzynski J, Zbikowska M, Palgan K: The serum immunoglobulin IgE, interleukin-4 and soluble form receptor CD23 dynamic changes in patients with hypercholesterolaemia II B treated with pravastatin (abstract). Eur Heart J 2000;21:155.
Libby P, Aikawa M, Kinlay S, Selwyn A, Ganz P: Lipid lowering improves endothelial functions. Int J Cardiol 2000;74(suppl 1):S3–S10.
Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connel JM: Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin Sci 2000;98:531–535.
Egashira K, inou T, Hirooka Y: Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993;91:29–37.
Treasure CB, Klein JL, Weintraub WS: Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481–487.
O’Driscoll GO, Hreen D, Taylor RR: Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95:1126–1131.
Mostaza JM, Gomez MV, Gallardo F: Cholesterol reduction improves myocardial perfusion abnormalities in normolipidemic patients with coronary artery disease (CAD) (abstract). Atherosclerosis 1999;144:33.
Eichstadt HW, Eskotter H, Hoffman I: Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease. Am J Cardiol 1995;76:122A–125A.
Anderson TJ, Meredith IT, Yeung AC: The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488–493.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Patterson Edens R, Latifi R, Dudrick SJ: Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomogaphy after dipyridamole in patients with coronary artery disease: A potential noninvasive marker of healing coronary endothelium. Circulation 1994;89:1530–1538.
De Man FH, Weverling AW, Smelt AH: Impaired endothelium-dependent vasodilation in the forearm of patients with endogenous hypertriglyceridemia: Reversal upon lipid-lowering therapy by atorvastatin (abstract). Circulation 1998;98:I-243.
Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E: Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–235.
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