Semin Vasc Med 2004; 4(4): 417-422
DOI: 10.1055/s-2004-869599
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Anti-inflammatory Properties of Statins

Sabine Steffens1 , Francois Mach1
  • 1Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Research, Geneva, Switzerland
Further Information

Publication History

Publication Date:
29 April 2005 (online)

ABSTRACT

Increasing clinical and experimental evidence indicates that some beneficial effects of statins, known as efficient therapeutic agents in cardiovascular disease treatment, may result from their ability to modulate vascular and endothelial cell gene expression by mechanisms independent of cholesterol reduction. It has been shown that statins exhibit direct anti-inflammatory properties via inhibition of proinflammatory cytokine and chemokine secretion, as well as through adhesion molecule expression on leukocytes. Another important mechanism by which statins may modulate the immune response is inhibition of interferon γ-induced expression of class II major histocompatibility complexes. Class II major histocompatibility complex expression is central to immune regulation in T cell-mediated autoimmune diseases, indicating a potential beneficial role of statins in these pathologies. Indeed, promising new preclinical data indicate that statins might be useful in the treatment of multiple sclerosis and rheumatoid arthritis.

REFERENCES

  • 1 LaRosa J C. What do the statins tell us?.  Am Heart J. 2002;  144 S21-S26
  • 2 Veillard N R, Mach F. Statins: the new aspirin?.  Cell Mol Life Sci. 2002;  59 1771-1786
  • 3 Libby P, Ridker P M, Maseri A. Inflammation and atherosclerosis.  Circulation. 2002;  105 1135-1143
  • 4 Lusis A J. Atherosclerosis.  Nature. 2000;  407 233-241
  • 5 Martin G, Duez H, Blanquart C et al.. Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.  J Clin Invest. 2001;  107 1423-1432
  • 6 Duez H, Fruchart J C, Staels B. PPARS in inflammation, atherosclerosis and thrombosis.  J Cardiovasc Risk. 2001;  8 187-194
  • 7 Wang N, Verna L, Chen N G et al.. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells.  J Biol Chem. 2002;  277 34176-34181
  • 8 Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation.  Cytokine Growth Factor Rev. 2002;  13 413-421
  • 9 Ortego M, Bustos C, Hernandez-Presa M A et al.. Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.  Atherosclerosis. 1999;  147 253-261
  • 10 Zelvyte I, Dominaitiene R, Crisby M, Janciauskiene S. Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro.  Pharmacol Res. 2002;  45 147-154
  • 11 Blake G J, Ridker P M. Novel clinical markers of vascular wall inflammation.  Circ Res. 2001;  89 763-771
  • 12 Zwaka T P, Hombach V, Torzewski J. C-Reactive protein-mediated low density lipoprotein uptake by macrophages. Implications for atherosclerosis.  Circulation. 2001;  103 1194-1197
  • 13 Kent S M, Flaherty P J, Coyle L C, Markwood T T, Taylor A J. Effect of atorvastatin and pravastatin on serum C-reactive protein.  Am Heart J. 2003;  145 e8
  • 14 Bickel C, Rupprecht H J, Blankenberg S et al.. Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease.  Am J Cardiol. 2002;  89 901-908
  • 15 Reape T J, Groot P H. Chemokines and atherosclerosis.  Atherosclerosis. 1999;  147 213-225
  • 16 Hayes I M, Jordan N J, Towers S et al.. Human vascular smooth muscle cells express receptors for CC chemokines.  Arterioscler Thromb Vasc Biol. 1998;  18 397-403
  • 17 Rezaie-Majd A, Maca T, Bucek R A 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 1194-1199
  • 18 Waehre T, Damas J K, Gullestad L et al.. Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease.  J Am Coll Cardiol. 2003;  41 1460-1467
  • 19 Nakashima Y, Raines E W, Plump A S, Breslow J L, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse.  Arterioscler Thromb Vasc Biol. 1998;  18 842-851
  • 20 Chung H K, Lee I K, Kang H et al.. Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells.  Exp Mol Med. 2002;  34 451-461
  • 21 Rezaie-Majd A, Prager G W, Bucek R A et al.. Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients.  Arterioscler Thromb Vasc Biol. 2003;  23 397-403
  • 22 Lutgens E, Daemen M J. CD40-CD40L interactions in atherosclerosis.  Trends Cardiovasc Med. 2002;  12 27-32
  • 23 Lutgens E, Gorelik L, Daemen M J et al.. Requirement for CD154 in the progression of atherosclerosis.  Nat Med. 1999;  5 1313-1316
  • 24 Mach F, Schonbeck U, Sukhova G K, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling.  Nature. 1998;  394 200-203
  • 25 Foy T M, Aruffo A, Bajorath J, Buhlmann J E, Noelle R J. Immune regulation by CD40 and its ligand GP39.  Annu Rev Immunol. 1996;  14 591-617
  • 26 Schonbeck U, Mach F, Libby P. CD154 (CD40 ligand).  Int J Biochem Cell Biol. 2000;  32 687-693
  • 27 Wagner A H, Gebauer M, Guldenzoph B, Hecker M. 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.  Arterioscler Thromb Vasc Biol. 2002;  22 1784-1789
  • 28 Mulhaupt F, Matter C M, Kwak B R et al.. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.  Cardiovasc Res. 2003;  59 755-766
  • 29 Bobryshev Y V, Lord R S. S-100 positive cells in human arterial intima and in atherosclerotic lesions.  Cardiovasc Res. 1995;  29 689-696
  • 30 Bobryshev Y V, Lord R S. Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of Vascular Dendritic Cells in athero-resistant and athero-prone areas of the normal aorta.  Arch Histol Cytol. 1995;  58 307-322
  • 31 Hackstein H, Thomson A W. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs.  Nat Rev Immunol. 2004;  4 24-34
  • 32 Bobryshev Y V, Lord R S. Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions.  Cardiovasc Res. 1998;  37 799-810
  • 33 Alderman C J, Bunyard P R, Chain B M, Foreman J C, Leake D S, Katz D R. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment?.  Cardiovasc Res. 2002;  55 806-819
  • 34 Aicher A, Heeschen C, Mohaupt M, Cooke J P, Zeiher A M, Dimmeler S. Nicotine strongly activates dendritic cell-mediated adaptive immunity: potential role for progression of atherosclerotic lesions.  Circulation. 2003;  107 604-611
  • 35 Weis M, Schlichting C L, Engleman E G, Cooke J P. Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases.  Arterioscler Thromb Vasc Biol. 2002;  22 1817-1823
  • 36 Yilmaz A, Reiss C, Tantawi O et al.. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis.  Atherosclerosis. 2004;  172 85-93
  • 37 Mach B, Steimle V, Martinez-Soria E, Reith W. Regulation of MHC class II genes: lessons from a disease.  Annu Rev Immunol. 1996;  14 301-331
  • 38 Steimle V, Otten L A, Zufferey M, Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome).  Cell. 1993;  75 135-146
  • 39 Steimle V, Siegrist C A, Mottet A, Lisowska-Grospierre B, Mach B. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA.  Science. 1994;  265 106-109
  • 40 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator.  Nat Med. 2000;  6 1399-1402
  • 41 Wenke K, Meiser B, Thiery J et al.. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial.  Circulation. 1997;  96 1398-1402
  • 42 Kobashigawa J A, Katznelson S, Laks H et al.. Effect of pravastatin on outcomes after cardiac transplantation.  N Engl J Med. 1995;  333 621-627
  • 43 Youssef S, Stuve O, Patarroyo J C et al.. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.  Nature. 2002;  420 78-84
  • 44 Aktas O, Waiczies S, Smorodchenko A et al.. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin.  J Exp Med. 2003;  197 725-733
  • 45 Leung B P, Sattar N, Crilly A et al.. A novel anti-inflammatory role for simvastatin in inflammatory arthritis.  J Immunol. 2003;  170 1524-1530
  • 46 Vollmer T, Key L, Durkalski V et al.. Oral simvastatin treatment in relapsing-remitting multiple sclerosis.  Lancet. 2004;  363 1607-1608
  • 47 McCarey D W, McInnes I B, Madhok R et al.. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial.  Lancet. 2004;  363 2015-2021
  • 48 Abud-Mendoza C, de la Fuente H, Cuevas-Orta E, Baranda L, Cruz-Rizo J, Gonzalez-Amaro R. Therapy with statins in patients with refractory rheumatic diseases: a preliminary study.  Lupus. 2003;  12 607-611
  • 49 Sukhova G K, Williams J K, Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.  Arterioscler Thromb Vasc Biol. 2002;  22 1452-1458
  • 50 Yilmaz A, Reiss C, Tantawi O et al.. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis.  Atherosclerosis. 2004;  172 85-93
  • 51 Kleemann R, Verschuren L, de Rooij B J et al.. Blood. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro.  Blood. 2004;  103 4188-4194
  • 52 Martin G, Duez H, Blanquart C et al.. Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.  J Clin Invest. 2001;  107 1423-1432

Francois MachM.D. 

Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches

64 Avenue Roseraie, 1211 Geneva, Switzerland

    >