Cardiovascular Drugs and Therapy

, Volume 23, Issue 3, pp 215–220 | Cite as

Native LDL-Cholesterol Mediated Monocyte Adhesion Molecule Overexpression is Blocked by Simvastatin

  • Carlos V. SerranoJr.
  • Antônio Eduardo Pesaro
  • James A. de Lemos
  • Fabiana Rached
  • C. Alexandre Segre
  • Fernando Gomes
  • Adriano F. Ribeiro
  • José Carlos Nicolau
  • Vanda M. Yoshida
  • Hugo P. Monteiro
Article

Abstract

Aim of the study

This study sought to evaluate the effect of nLDL concentrations on monocyte adhesion molecule expression in hypercholesterolemic patients with stable coronary artery disease (CAD) and to determine whether lipid-lowering therapy with simvastatin would change this effect.

Methods

Blood samples from patients with hypercholesterolemia (mean LDL 152 mg/dL) and CAD (HC, n = 23) were collected before and after a 12-week treatment with 40 mg of simvastatin. Healthy individuals (mean LDL 111 mg/dL) were used as controls (CT, n = 15). Isolated nLDL, at a fixed concentration of 100 mg/dL, was added to monocyte suspensions obtained before and after the simvastatin treatment. Monocyte activation was determined by changes in cellular adhesion molecule expression.

Results

In response to nLDL, CD11b and CD14 adhesion molecule expression was higher in HC patients than in CT patients before treatment (174.2 ± 8.4 vs 102.2 ± 6.3, P < 0.03 and 140.4 ± 5.0 vs 90.4 ± 6.7, P < 0.04). After simvastatin treatment, CD11b expression decreased to 116.9 ± 12.5 (P < 0.03) and CD14 expression to 107.5 ± 6.2 (P < 0.04). Alternatively, L-selectin expression was lower in HC patients than in CT patients before therapy (46.0 ± 3.5 vs 62.1 ± 5.5, P < 0.04), and it increased markedly after lipid reduction to 58.7 ± 5.0 (P < 0.04 vs baseline). After simvastatin treatment, LDL was reduced to mean 101.5 mg/dL.

Conclusions

These data demonstrate that monocytes from HC patients are more prone to marked nLDL-mediated changes of adhesion molecule expression than monocytes from controls. Simvastatin is capable of inhibiting such nLDL effects. This proinflammatory response to nLDL may have a role in the early onset of atherosclerosis.

Key words

Native LDL-cholesterol Adhesion molecules Monocyte Simvastatin Atherosclerosis Inflammation 

References

  1. 1.
    Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Faruqi RM, DiCorleto PE. Mechanisms of monocyte recruitment and accumulation. Br Heart J 1993;69:S19–29.PubMedCrossRefGoogle Scholar
  3. 3.
    Miller YI, Chang MK, Binder CJ, Shaw PX, Witztum JL. Oxidized low density lipoprotein and innate immune receptors. Curr Opin Lipidol 2003;14:437–45.PubMedCrossRefGoogle Scholar
  4. 4.
    Thomas MK, Narang D, Lakshmy R, Gupta R, Naik N, Maulik SK. Correlation between inflammation and oxidative stress in normocholesterolemic coronary artery disease patients ‘on’ and ‘off’ atorvastatin for short time intervals. Cardiovasc Drugs Ther 2006;20:37–44.PubMedCrossRefGoogle Scholar
  5. 5.
    Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005;111:3481–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Fosterga J, Nilsson J, Haegerstrand A, Hamsten A, Wigzell A, Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and monocytic cell line U937. Proc Natl Acad Sci USA 1990;87:904–8.CrossRefGoogle Scholar
  7. 7.
    Smalley DM, Lin JH, Curtis ML, Kobari Y, Stemerman MB, Pritchard KA Jr. Native LDL increases endothelial cell adhesiveness by inducing intercellular adhesion molecule-1. Arterioscler Thromb Vasc Biol 1996;16:585–90.PubMedGoogle Scholar
  8. 8.
    Han KH, Tangirala RK, Green SR, Quehenberger O. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes: a regulatory role for plasma LDL. Arterioscler Thromb Vasc Biol 1998;18:1983–91.PubMedGoogle Scholar
  9. 9.
    Kreuzer J, Denger S, Jahn L, Ritter K, von Hodenberg E, Kubler W. LDL stimulates chemotaxis of human monocytes through a cyclooxygenase-dependent pathway. Arterioscler Thromb Vasc Biol 1996;16:1481–7.PubMedGoogle Scholar
  10. 10.
    Pritchard KA Jr, Tota RR, Lin JH, Danishefsky KJ, Kurilla BA, Holland JA, Stemerman MB. Native low density lipoprotein: endothelial cell recruitment of mononuclear cells. Arterioscler Thromb Vasc Biol 1991;11:1175–81.Google Scholar
  11. 11.
    Allen S, Khan S, Al-Mohanna F, Batten P, Yacoub M. Native low-density lipoprotein-induced calcium transients trigger VCAM-1 and E-selectin expression in cultured human vascular endothelial cells. J Clin Invest 1998;101:1064–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Jang Y, Lincoff M, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994;24:1591–601.PubMedCrossRefGoogle Scholar
  13. 13.
    Frenette PS, Wagner DD. Adhesion molecules—part II: blood vessels and blood cells. N Engl J Med 1996;335:43–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Haziot A, Chen S, Ferrero E, Low MG, Silber R, Goyert SM. The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J Immunol 1988;141:547–52.PubMedGoogle Scholar
  15. 15.
    Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230–5.PubMedGoogle Scholar
  16. 16.
    Nissen SE, Tuzcu EM, Schoenhagen P. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Endres M. Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 2006;7:31–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:39–43.Google Scholar
  19. 19.
    César LAM. Diretriz de angina estável. Arq Bras Cardiol 2004;83:1–44.CrossRefGoogle Scholar
  20. 20.
    Fogelman AM, Elahi F, Sykes K, Van Lenten BJ, Territo MC, Berliner JA. A modification of the Recalde method for the isolation of human monocytes. J Lipid Res 1988;29:1243–7.PubMedGoogle Scholar
  21. 21.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. J Biol Chem 1951;193:265–75.PubMedGoogle Scholar
  22. 22.
    Serrano CV Jr, Yoshida VM, Venturinelli ML, D’ Amico E, Monteiro HP, Ramires JAF, Luz PL. Effect of simvastatin on monocyte adhesion molecule expression in patients with hypercholesterolemia. Atherosclerosis 2001;157:505–12.PubMedCrossRefGoogle Scholar
  23. 23.
    O’Byrne D, Devaraj S, Islam KN, Collazo R, McDonald L, Grundy S, Jialal I. Low-density lipoprotein (LDL)-induced monocyte-endothelial cell adhesion, soluble cell adhesion molecules, and autoantibodies to oxidized-LDL in chronic renal failure patients on dialysis therapy. Metabolism 2001;50:207–15.PubMedCrossRefGoogle Scholar
  24. 24.
    SAS Institute Inc.. SAS Procedures Guide for Personal Computers. Version 6 ed.. Cary, NC: SAS Institute Inc.; 1985.Google Scholar
  25. 25.
    Packard RRS, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem 2008;54:24–38.PubMedCrossRefGoogle Scholar
  26. 26.
    Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–26.PubMedCrossRefGoogle Scholar
  27. 27.
    Navab MSS, Ines SY, Hama GP, Hough LA, Ross R, Bork W, Valente AJ, Berliner JA, Drinkwater DC, Laks H, Fogelman AM. Monocyte transmigration induced by modification of low density lipoprotein in coculture of human aortic wall cells is due to induction of MCP-1 and abolished by high density lipoprotein. J Clin Invest 1991;88:2039–46.PubMedCrossRefGoogle Scholar
  28. 28.
    Khan BV, Partharasathy SS, Alexander RW, Medford RM. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest 1995;95:1262–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991;251:788–96.PubMedCrossRefGoogle Scholar
  30. 30.
    Netea MG, Kullberg BJ, Demacker PNM, Jacobs LEH, Verver-Jansen TJG, Hijmans A, van Tits LHJ, Hoenderop JGJ, Willems PHGM, van der Meer JWM, Stalenhoef AFH. Native LDL potentiate TNF and IL-8 production by human mononuclear cells. J Lipid Res 2002;43:1065–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Aplin AE, Howe A, Alahari SK, Juliano RL. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol Rev 1998;50:197–264.PubMedGoogle Scholar
  32. 32.
    Sluiter W, Pietersma A, Lamers JMJ, Koster JF. Leukocyte adhesion molecules on the vascular endothelium: their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. J Cardiovasc Pharmacol 1993;22:S37–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Adams DH, Shaw S. Leukocyte-endothelial interactions and regulation of leukocyte migration. Lancet 1994;343:831–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Verna L, Ganda C, Stemerman MB. In vivo low-density lipoprotein exposure induces intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 correlated with activator protein-1 expression. Arterioscler Thromb Vasc Biol 2006;26:1344–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Aikawa M, Libby P. Lipid lowering therapy in atherosclerosis. Semin Vasc Med 2004;4:357–66.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Carlos V. SerranoJr.
    • 1
  • Antônio Eduardo Pesaro
    • 1
  • James A. de Lemos
    • 2
  • Fabiana Rached
    • 1
  • C. Alexandre Segre
    • 1
  • Fernando Gomes
    • 1
  • Adriano F. Ribeiro
    • 1
  • José Carlos Nicolau
    • 1
  • Vanda M. Yoshida
    • 1
  • Hugo P. Monteiro
    • 3
  1. 1.Heart Institute (InCor) HCFMUSP, Medical SchoolUniversity of São PauloSão PauloBrazil
  2. 2.University of Texas Southwestern Medical CenterDallasUSA
  3. 3.Molecular Biochemistry/Biology DepartmentSão Paulo Federal University/Paulista School of Medicine–CINTERGENSão PauloBrazil

Personalised recommendations