User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Rosuvastatin restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice

Primary tabs

download
  • Open access
  • PDF
  • 190.56 K
Verreth, W. De Keyzer, D. Davey, P. C. Geeraert, B. Mertens, A. Desjardins, Fanny [UCL] Balligand, Jean-Luc [UCL] Holvoet, P.

BACKGROUND AND PURPOSE: Our goal was to elucidate mechanisms of the inhibitory effect of rosuvastatin on the accumulation of plaque oxidized low density lipoproteins (oxLDL) and on plaque volume, without lowering cholesterol, in mice with combined leptin and LDL-receptor deficiency (DKO). EXPERIMENTAL APPROACH: Twelve-week old DKO mice were treated with rosuvastatin (10 mg kg(-1) day(-1), s.c.) or placebo or no treatment for 12 weeks. The effect on blood variables, aortic plaque volume and composition and gene expression in the aorta and in THP-1 cells was assessed. KEY RESULTS: Rosuvastatin lowered free fatty acids (FFA), triglycerides, and increased insulin sensitivity, without affecting cholesterol. Rosuvastatin lowered the plaque volume, inhibited macrophage, lipid and oxLDL accumulation, and decreased the oxLDL-to-LDL ratio of plaques in the aortic arch. It increased superoxide dismutase 1 (SOD1), CD36, LXR-alpha, ABCA-1 and PPAR-gamma RNA expression in aortic extracts. SOD1 was the strongest inverse correlate of oxLDL. In THP-1 macrophages and foam cells, expression of SOD1 was lower than in THP-1 monocytes. Rosuvastatin restored expression of SOD1 in THP-1 macrophages and foam cells. CONCLUSIONS AND IMPLICATIONS: Rosuvastatin restored SOD1 expression in THP-1 macrophages and foam cells in vitro and in the aorta of DKO mice. The latter was associated with less oxLDL accumulation within atherosclerotic plaques and inhibition of plaque progression. This effect was obtained at a dose not affecting cholesterol levels but improving insulin sensitivity. SOD1 is a potentially important mediator of the prevention of oxLDL accumulation within atherosclerotic plaques.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2007
Journal information "British Journal of Pharmacology" - Vol. 151, no. 3, p. 347-355 (2007)
Peer reviewed yes
Publisher JohnWiley & Sons Ltd. (Chichester)
issn 0007-1188
e-issn 1476-5381
Publication status Publié
Affiliations UCL - MD/MINT - Département de médecine interne
UCL - (SLuc) Service de médecine interne et maladies infectieuses (MIMI)
MESH Subject Animals ; Aorta - drug effects - metabolism - pathology ; Atherosclerosis - metabolism - pathology - prevention & control ; Blood Glucose - metabolism ; Body Weight ; Cell Line ; Dyslipidemias - blood - genetics - physiopathology ; Fluorobenzenes - pharmacology ; Gene Expression - drug effects ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Insulin - blood ; Leptin - deficiency - genetics ; Lipids - blood ; Lipoproteins, LDL - metabolism ; Macrophages - cytology - drug effects - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Obese ; Obesity - blood - genetics - physiopathology ; PPAR gamma - genetics ; Pyrimidines - pharmacology ; Receptors, LDL - deficiency - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfonamides - pharmacology ; Superoxide Dismutase - genetics - metabolism
Keywords Atherosclerosis ; Cholesterol ; Lipoproteins ; Metabolic syndrome ; Obesity ; Superoxide dismutase
Links
  1. Argmann, J Biol Chem, 280, 22212 (2005)
  2. Chawla, Mol Cell, 7, 161 (2001)
  3. Costa, Diabet Med, 20, 743 (2003)
  4. Crisby M., Nordin-Fredriksson G., Shah P. K., Yano J., Zhu J., Nilsson J., Pravastatin Treatment Increases Collagen Content and Decreases Lipid Content, Inflammation, Metalloproteinases, and Cell Death in Human Carotid Plaques : Implications for Plaque Stabilization, 10.1161/01.cir.103.7.926
  5. Didion, Circ Res, 91, 938 (2002)
  6. Fang X., Weintraub N. L., Rios C. D., Chappell D. A., Zwacka R. M., Engelhardt J. F., Oberley L. W., Yan T., Heistad D. D., Spector A. A., Overexpression of Human Superoxide Dismutase Inhibits Oxidation of Low-Density Lipoprotein by Endothelial Cells, 10.1161/01.res.82.12.1289
  7. Faraci, Arterioscler Thromb Vasc Biol, 24, 1367 (2004)
  8. Fukushima, Cardiovasc Res, 69, 459 (2006)
  9. Grip, Inflamm Res, 51, 58 (2002)
  10. Guclu, Biomed Pharmacother, 58, 614 (2004)
  11. Hasty, J Biol Chem, 276, 37402 (2001)
  12. Holvoet, Arterioscler Thromb Vasc Biol, 26, 1558 (2006)
  13. Holvoet, Diabetes, 53, 1068 (2004)
  14. Holvoet P., Vanhaecke J., Janssens S., Van de Werf F., Collen D., Oxidized LDL and Malondialdehyde-Modified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease, 10.1161/01.cir.98.15.1487
  15. Inoue, Life Sci, 67, 863 (2000)
  16. Kleemann, Circulation, 108, 1368 (2003)
  17. Libby, Am J Cardiol, 91, 4B (2003)
  18. Ludwig, J Clin Invest, 107, 379 (2001)
  19. Lundbye, Curr Atheroscler Rep, 7, 17 (2005)
  20. Mackness, Arterioscler Thromb Vasc Biol, 26, 1545 (2006)
  21. Mertens, Circulation, 107, 1640 (2003)
  22. Paniagua, Diabetes, 51, 2596 (2002)
  23. Parker, Atherosclerosis, 169, 19 (2003)
  24. Rosenson, Atherosclerosis, 173, 1 (2004)
  25. Schonbeck, Circulation, 109, II18 (2004)
  26. Sonmez, Endocrine, 22, 151 (2003)
  27. Staels, Curr Med Res Opin, 21, S13 (2005)
  28. Stoll, Timely Top Med Cardiovasc Dis, 9, E1 (2005)
  29. Takemoto, Arterioscler Thromb Vasc Biol, 21, 1712 (2001)
  30. Tanaka, Circulation, 110, II200 (2004)
  31. Tsimikas, N Engl J Med, 353, 46 (2005)
  32. Tsimikas S., Palinski W., Witztum J. L., Circulating Autoantibodies to Oxidized LDL Correlate With Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor-Deficient Mice, 10.1161/01.atv.21.1.95
  33. Umeji, Am J Physiol Heart Circ Physiol, 291, H2522 (2006)
  34. Usui, J Lipid Res, 43, 805 (2002)
  35. Eck, J Biol Chem, 278, 23699 (2003)
  36. Verreth, Circulation, 110, 3259 (2004)
  37. Verreth, Arterioscler Thromb Vasc Biol, 26, 922 (2006)
  38. Wagner A. H., Kohler T., Ruckschloss U., Just I., Hecker M., Improvement of Nitric Oxide-Dependent Vasodilatation by HMG-CoA Reductase Inhibitors Through Attenuation of Endothelial Superoxide Anion Formation, 10.1161/01.atv.20.1.61
  39. Wang, Proc Natl Acad Sci USA, 95, 4556 (1998)
Bibliographic reference Verreth, W. ; De Keyzer, D. ; Davey, P. C. ; Geeraert, B. ; Mertens, A. ; et. al. Rosuvastatin restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice. In: British Journal of Pharmacology, Vol. 151, no. 3, p. 347-355 (2007)
Permanent URL http://hdl.handle.net/2078.1/28573