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Effects of atorvastatin, simvastatin, and fenofibrate therapy on monocyte chemoattractant protein-1 secretion in patients with hyperlipidemia

  • Pharmacodynamics
  • Published:
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Abstract

Objective

Monocytes that migrate into the arterial wall participate in the development and, eventually, rupture of the atherosclerotic plaque. The aim of this study was to evaluate the secretion of monocyte chemoattractant protein-1 (MCP-1) by monocytes from hyperlipidemic patients treated with hypolipidemic drugs, namely fenofibrate, simvastatin, or atorvastatin to determine what role is played by these drugs in the development and stabilization of the atherosclerotic plaque.

Methods

Fifty-four hyperlipidemic patients, who did not respond to a low-fat diet, were treated with fenofibrate, simvastatin, or atorvastatin (18 patients in each group) for 1 month. The control group included 18 normolipidemic, healthy, age-matched participants. Ten hyperlipidemic patients were effectively treated with hypolipidemic diet alone for 1 month. This group was compared with a control group of ten healthy subjects. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. Before and after treatment, monocytes were isolated from peripheral blood. After stimulation with lipopolysaccharide (LPS), MCP-1 secretion was measured by enzyme-linked immunosorbent assay (ELISA).

Results

MCP-1 levels were significantly higher in hyperlipidemic patients than controls: 15.8±0.47, 16.7±0.23, and 14.9±0.45 compared with 12.36±0.42 ng/ml. Fenofibrate, atorvastatin, and simvastatin significantly decreased MCP-1 levels from 15.8±0.47 to 8.79±0.89, from 16.7±0.23 to 7.46±0.73, and from 14.9±0.45 to 10.3±0.8 ng/ml, respectively. In the diet-treated group of hyperlipidemic patients, the level of MCP-1 before therapy was significantly higher than in controls (16.89±0.31 vs 12.45±0.36 ng/ml). The diet therapy caused a significant decrease in levels of MCP-1 to 15.1±0.36 ng/ml. There was a correlation between the decreased levels of lipids and the decreased release of MCP-1 in the patients treated with hypolipemic drugs.

Conclusion

The drug-induced decrease in MCP-1 secretion in hyperlipidemic patients suggests that, apart from acting on lipids, the hypolipidemic drugs studied may directly inhibit the activity of monocytes.

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References

  1. Libby P, Hansson GK (1991) Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest 64:5–15

    CAS  PubMed  Google Scholar 

  2. Ross R (1991) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809

    Google Scholar 

  3. Takahashi M, Masuyama JI, Ikeda U et al. (1995) Induction of monocyte chemoattractant protein-1 synthesis in human monocytes during transendothelial migration in vitro. Circ Res 76:750–757

    CAS  PubMed  Google Scholar 

  4. Steinberg D, Lewis A (1997) Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071

    PubMed  Google Scholar 

  5. Yla-Herttuala S, Lipton BA, Rosenfeld ME et al. (1991) Expression of monocyte chemotactic protein-1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA 88:5252–5256

    CAS  PubMed  Google Scholar 

  6. Gosling J, Slaymaker S, Gu L et al. (1999) MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 103:773–778

    CAS  PubMed  Google Scholar 

  7. Boring L, Gosling J, Cleary M, Charo IF (1998) Decreased lesion formation in CCR2-mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394:894–897

    Article  CAS  PubMed  Google Scholar 

  8. Madej A, Okopień B, Kowalski J et al. (1998) Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int J Clin Pharm Ther 36:345–349

    CAS  Google Scholar 

  9. Abe Y, El Masri B, Kimball KT et al. (1998) Soluble adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion. Arterioscler Thromb Vasc Biol 18:723–731

    Google Scholar 

  10. Hackman A, Abe Y, Insull W Jr et al. (1996) Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation 93:1334–1338

    CAS  PubMed  Google Scholar 

  11. Kowalski J, Okopień B, Madej A, Makowiecka K, Zieliński M, Kalina Z, Herman ZS (2001) Levels of sICAM-1, sVCAM-1 and MCP-1 in patients with hyperlipoproteinemia IIa and IIb. Int J Clin Pharm Ther 39:48–52

    CAS  Google Scholar 

  12. Fruebis J, Gonzales V, Silvestre M, Palinski W (1997) Effect of probucol treatment on gene expression of VCAM-1, MCP-1 and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis. Arterioscler Thromb Vasc Biol 17:1289–302

    Google Scholar 

  13. Weber C, Erl W, Weber KS, Weber PC (1999) Effect of oxidized low-density lipoprotein, lipid mediators and statins on vascular cell interactions. Clin Chem Lab Med 37:243–251

    CAS  PubMed  Google Scholar 

  14. International Task Force for Prevention of Coronary Heart Disease (1992) Prevention of coronary heart disease. Scientific background and new clinical guidelines. Recommendation of the European Atherosclerosis Society. Nutr Metab Cardiovasc Dis 2:113–156

    Google Scholar 

  15. Flo RW, Naess A, Lund-Johansen F, Maehle BO, Sjursen H, Lehmann V, Solberg CO (1991) Negative selection of human monocytes using magnetic particles covered by anti-lymphocyte antibodies. J Immunol Methods 137:89–94

    Article  CAS  PubMed  Google Scholar 

  16. Reckless J, Rubin EM, Verstuyft JB, Metcalfe JC, Grainer DJ (1999) Monocyte chemoattractant protein-1 but not tumor necrosis factor-α is correlated with monocyte infiltration in mouse lipid lesions. Circulation 99:2310–2316

    CAS  PubMed  Google Scholar 

  17. Sakai M, Kobori S, Matsumura T et al. (1997) HMG-CoA reductase inhibitors suppress macrophage growth induced by oxidized low-density lipoprotein. Atherosclerosis 133:51–59

    Article  CAS  PubMed  Google Scholar 

  18. Davies MJ, Thomas AC (1985) Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death and crescendo angina. Br Heart J 53:363–373

    CAS  PubMed  Google Scholar 

  19. Falk E, Shah PK, Fuster V (1995) Coronary plaque disruption. Circulation 92:657–671

    CAS  Google Scholar 

  20. Libby P (1995) Molecular basis of acute coronary syndromes. Circulation 91:2844–2850

    CAS  PubMed  Google Scholar 

  21. Park YS, Guijarro C, Kim Y, Massy ZA, Kasiske BL, Keane WF, O'Donnell MP (1998) Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats. Am J Kidney Dis 31:190–194

    CAS  PubMed  Google Scholar 

  22. Morikawa S, Takabe W, Mataki C, Kanke T, Itoh T, Wada Y, Izumi A, Saito Y, Hamakubo T, Kodama T (2002) The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. J Atheroscler Thromb 9:178–183

    CAS  PubMed  Google Scholar 

  23. Rezaie-Majd A, Maca T, Bucek RA, Valant P, Muller M, Husslein P, Kashanipour A, Minar E, Baghestanian M (2002) Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 22:1194–1199

    Google Scholar 

  24. Grip O, Janciauskiene S, Lindgren S (2002) Atorvastatin activates PPAR-gamma and attenuates the inflammatory response in human monocytes. Inflamm Res 51:58–62

    CAS  PubMed  Google Scholar 

  25. Pahan K, Sheikh FG, Namboodiri AM, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia and macrophages. J Clin Invest 100:2671–2679

    CAS  PubMed  Google Scholar 

  26. Pasceri V, Cheng SJ, Willerson JT, Yech ET, Chang J (2001) Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 103:2531–2534

    CAS  PubMed  Google Scholar 

  27. Bustos C, Hernandez-Presa MA, Ortego M et al. (1998) HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in rabbit model of atherosclerosis. J Am Coll Cardiol 32:2057–2064

    Article  CAS  PubMed  Google Scholar 

  28. Ortego M, Bustos C, Hernandez-Presa MA, Tunon J, Diaz C, Hernandez G, Egido J (1999) Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 147:253–261

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Medical University of Silesia, 40–752 Katowice, 18, Medyków, Poland

    J. Kowalski, B. Okopień, A. Madej, M. Zieliński, D. Belowski, Z. Kalina & Z. S. Herman

  2. Second Department of Internal Diseases and Clinical Pharmacology, Medical University of Silesia, 40–752 Katowice, 18, Medyków, Poland

    Z. Kalina

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  1. J. Kowalski
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  2. B. Okopień
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  3. A. Madej
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  4. M. Zieliński
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  5. D. Belowski
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  6. Z. Kalina
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  7. Z. S. Herman
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Correspondence to J. Kowalski.

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Kowalski, J., Okopień, B., Madej, A. et al. Effects of atorvastatin, simvastatin, and fenofibrate therapy on monocyte chemoattractant protein-1 secretion in patients with hyperlipidemia. Eur J Clin Pharmacol 59, 189–193 (2003). https://doi.org/10.1007/s00228-003-0581-7

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  • DOI: https://doi.org/10.1007/s00228-003-0581-7

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