Apart from reducing systemic lipid levels, statins may improve the clinical course of atherosclerosis by exerting favourable pleiotropic effects on the vessel wall.We studied the effects of rosuvastatin, a new, potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on vascular remodelling after endothelial injury in the hyperlipidaemic apolipoprotein E-knockout (apoE-/-) mouse. ApoE-/- mice, 22-weeks-old, were injected daily with rosuvastatin at a low (1 mg/kg; n=27) or high dosage (10 mg/kg; n=24), or with vehicle alone (n=26).After treatment for 2 weeks,endothelial injury and thrombosis of the carotid artery was induced with 10% ferric chloride.Treatment was then resumed for a 3-week period.Although statin treatment did not affect the plasma lipid levels of mice, mean times to arterial thrombosis were prolonged in the low-dose and the high-dose group compared to controls (P<0.05 and P<0.01 respectively). Interestingly, rosuvastatin withdrawal 4 days before injury completely reversed the antithrombotic effects of the drug. In follow-up studies 3 weeks after injury,deposition of fibrin in the vessel wall was significantly reduced in the rosuvastatin-treated animals. There was an increase in the content of α -actin-positive smooth muscle cells (P =0.008) and collagen fibers (P<0.001), and a concomitant decrease in the number of oxLDL-containing macrophages (P<0.001). Overall, the neointimal area and the severity of luminal stenosis were significantly reduced in statin-treated mice. Thus, rosuvastatin attenuates arterial thrombosis and neointima formation, and it may stabilise vascular lesions developing after endothelial injury in mice.These effects are independent of systemic lipid lowering.
2 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486-97.
6 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.
7
Schwartz GG,
Olsson AG,
Ezekowitz MD.
et al Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711-8.
8
Scalia R,
Gooszen ME,
Jones SP.
et al Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 2001; 103: 2598-603.
9
Sparrow CP,
Burton CA,
Hernandez M.
et al Simvastatin has anti-inflammatory and anti-atherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol 2001; 21: 115-21.
10
Bea F,
Blessing E,
Bennett B.
et al Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice independently of lipid lowering. Arterioscler Thromb Vasc Biol 2002; 22: 1832-7.
11
Wang YX,
Martin-McNulty B,
Huw LY.
et al Anti-atherosclerotic effect of simvastatin depends on the presence of apolipoprotein E. Atherosclerosis 2002; 162: 23-31.
12
Luttun A,
Lupu F,
Storkebaum E.
et al Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipo-protein E-deficient mice. Arterioscler Thromb Vasc Biol 2002; 22: 499-505.
13
Eitzman DT,
Westrick RJ,
Xu Z.
et al Plasminogen activator inhibitor-1 deficiency pro-tects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96: 4212-5.
14
Sjoland H,
Eitzman DT,
Gordon D.
et al Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2000; 20: 846-52.
15
Schäfer K,
Konstantinides S,
Riedel C.
et al Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase- or tissue- type plasminogen activator. Circulation 2002; 106: 1847-52.
16
Burke AP,
Kolodgie FD,
Farb A.
et al Healed plaque ruptures and sudden coronary death : evidence that subclinical rupture has a role in plaque progression. Circulation 2001; 103: 934-40.
18
Schäfer K,
Müller K,
Hecke A.
et al Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2003; 23: 2097-103.
20
Paoletti R,
Fahmy M,
Mahla G.
et al Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study. J Cardiovasc Risk 2001; 8: 383-90.
21
Konstantinides S,
Schäfer K,
Thinnes T.
et al Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice. Circulation 2001; 103: 576-83.
22
Pynn M,
Schäfer K,
Konstantinides S.
et al Exercise training reduces neointimal growth and stabilizes vascular lesions developing after injury in apolipoprotein E-deficient mice. Circulation 2004; 109: 386-92.
23
Aikawa M,
Rabkin E,
Okada Y.
et al Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation 1998; 97: 2433-44.
24
Konstantinides S,
Schäfer K,
Koschnick S.
et al Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-40.
25
Corti R,
Fayad ZA,
Fuster V.
et al Effects of lipidlowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001; 104: 249-52.
26
Crisby M,
Nordin-Fredriksson G,
Shah PK.
et al Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques : implications for plaque stabilization. Circulation 2001; 103: 926-33.
27
Aikawa M,
Rabkin E,
Sugiyama S.
et al An HMGCoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103: 276-83.
28
Ridker PM.
Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003; 108: 2292-7.
29
Laufs U,
Gertz K,
Dirnagl U.
et al Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res 2002; 942: 23-30.
30
Laufs U,
Endres M,
Custodis F.
et al Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation 2000; 102: 3104-10.
32
Werner N,
Priller J,
Laufs U.
et al Bone marrowderived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy- 3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol 2002; 22: 1567-72.
33
Kleemann R,
Princen HM,
Emeis JJ.
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 2003; 108: 1368-74.
34
Laufs U,
Gertz K,
Huang P.
et al Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in nor-mocholesterolemic mice. Stroke 2000; 31: 2442-9.
35
Cipollone F,
Mezzetti A,
Porreca E.
et al Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106: 399-402.
39
Walter DH,
Rittig K,
Bahlmann FH.
et al Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow- derived endothelial progenitor cells. Circulation 2002; 105: 3017-24.
40
Vasa M,
Fichtlscherer S,
Adler K.
et al Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103: 2885-90.
42
Ploplis VA,
Cornelissen I,
Sandoval-Cooper MJ.
et al Remodeling of the vessel wall after copper-induced injury is highly attenuated in mice with a total deficiency of plasminogen activator inhibitor-1. Am J Pathol 2001; 158: 107-17.
44
Eto M,
Kozai T,
Cosentino F.
et al Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation 2002; 105: 1756-9.
46
Bea F,
Blessing E,
Shelley I M.
et al Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering: potential role of simvastatin- mediated inhibition of Egr-1 expression and activation. Atherosclerosis 2003; 167: 187-94.
