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. 2006 Dec 5;28(9):423–428. doi: 10.1002/clc.4960280907

Effects of fluvastatin, an HMG‐CoA reductase inhibitor, on serum levels of interleukin‐18 and matrix metalloproteinase‐9 in patients with hypercholesterolemia

Hsin‐Bang Leu 1, Jaw‐Wen Chen 1, Tao‐Cheng Wu 1, Yu‐An Ding 1, Shing‐Jong Lin 1, Min‐Ji Charng 1,✉
PMCID: PMC6654498  PMID: 16250265

Abstract

Background: Interleukin‐18 (IL‐18), a novel proinflammatory marker, and matrix metalloproteinaolemia.

Hypothesis: The study was designed to investigate the influence of statin therapy in circulating IL‐18, MMP‐9, and endothelial function.

Methods: We investigated the effects of a 12‐week therapy with fluvastatin on IL‐18, MMP‐9, and endothelial function in patients with hypercholesterolemia.

Results: Compared with placebo, fluvastatin significantly improved flow‐mediated vasodilatation to hyperemia, a hallmark of endothelial function [from 3.8% (−3.9 ∼ 15.2) to 5.9% (−0.3 ∼ 13.2), p = 0.001], and attenuated plasma levels of high sensitivity C‐reactive protein (hsCRP) [from 1.3 (0.3 ∼ 7.7) to 1.1 mg/l (0.2 ∼ 3.5), p = 0.018], IL‐18 [from 247.6 (145.4 ∼ 378.4) to 196.4 pg/dl (90.7 ∼ 380.2), p < 0.001], total MMP‐9 (from 58 ± 46.3 to 39.4 ± 22.4 ng/dl, p = 0.023), and MMP‐9 activity [from 6.4 (3.6∼27) to 5.6 ng/dl (3.1∼13.7)]. However, no significant correlation was found between the degree of changes in lipid profile and flow‐mediated dilatation (FMD) and plasma concentration of IL‐18 and MMP‐9.

Conclusions: Fluvastatin reduced plasma concentrations of IL‐18 and MMP‐9, and improved endothelial function in patients with hypercholesterolemia independent of its lipid‐lowering effect.

Keywords: interleukin‐18, matrix metalloproteinase‐9, flow‐mediated vasodilatation, hypercholesterolemia, interferon‐γ

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References

  • 1. Ross R: Atherosclerosis: An inflammatory disease. N Engl J Med 1999; 340: 115–126 [DOI] [PubMed] [Google Scholar]
  • 2. Libby P: Molecular bases of the acute coronary syndromes. Circulation 1995; 91: 2844–2850 [DOI] [PubMed] [Google Scholar]
  • 3. Mallat Z, Corbaz A, Scoazec A, Besnard S, Tedgui A: Expression of interleukin‐18 in human atherosclerotic plaques and relation to plaque instability. Circulation 2001; 104: 1598–1603 [DOI] [PubMed] [Google Scholar]
  • 4. Mallat Z, Henry P, Fressonnet R, Alouani S, Beaufils P, Chvatchko Y, Tedgui A: Increased plasma concentrations of interleukin‐18 in acute coronary syndromes. Heart 2002; 88: 467–469 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Blankenberg S, Tiret L, Bickel C, Peetz D, Cambien F, Meyer J, Rupprecht HJ: Interleukin‐18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 2002; 106: 24–30 [DOI] [PubMed] [Google Scholar]
  • 6. Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994; 94: 2493–2503 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Cambien F, Tiret L: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003; 107: 1579–1585 [DOI] [PubMed] [Google Scholar]
  • 8. Esposito K, Pontillo A, Ciotola M, Di Palo C, Grella E, Nicoletti G, Giugliano D: Weight loss reduces interleukin‐18 levels in obese women. J Clin Endocrinol Metab 2002; 87: 3864–3866 [DOI] [PubMed] [Google Scholar]
  • 9. Esposito K, Nappo F, Giugliano F, Di Palo C, Paolisso G, Giugliano D: Meal modulation of circulating interleukin‐18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus. Am J Clin Nutr 2003; 78: 1135–1140 [DOI] [PubMed] [Google Scholar]
  • 10. Son JW, Koh KK, Ahn JY, Shin EK: Effects of statin on plaque stability and thrombogenicity in hypercholesterolemic patients with coronary artery disease. Int J Cardiol 2003; 88: 77–82 [DOI] [PubMed] [Google Scholar]
  • 11. Koh KK: Effects of statins on vascular wall: Vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000; 47: 648–657 [DOI] [PubMed] [Google Scholar]
  • 12. Luan Z, Chase AJ, Newby AC: Statins inhibit secretion of metalloproteinases‐1, ‐2, ‐3, and ‐9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol 2003; 23: 769–775 [DOI] [PubMed] [Google Scholar]
  • 13. Koh KK, Son JW, Ahn JY, Jeong EM, Choi IS, Shin EK: Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002; 22: E19–23 [DOI] [PubMed] [Google Scholar]
  • 14. Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE, Palmisano J: A community‐based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: The ezetimibe add‐on to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005; 80 (5): 587–595 [DOI] [PubMed] [Google Scholar]
  • 15. O'Rourke B, Barbir M, Mitchell AG, Yacoub MH, Banner NR: Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: Results of a randomised double‐blind, placebo‐controlled study. Int J Cardiol 2004; 94: 235–240 [DOI] [PubMed] [Google Scholar]
  • 16. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Creager MA, Deanfield J, Vita J, Vogel R, and the International Brachial Artery Reactivity Task Force : Guidelines for the ultrasound assessment of endothelial‐dependent, flow‐mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002; 39: 257–265 [DOI] [PubMed] [Google Scholar]
  • 17. Lu TM, Ding YA, Leu HB, Yin WH, Sheu WH, Chu KM: Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol 2004; 94: 157–161 [DOI] [PubMed] [Google Scholar]
  • 18. Huang PH, Leu HB, Chen JW, Cheng CM, Huang CY, Tuan TC, Ding PY, Lin SJ: Usefulness of attenuated heart rate recovery immediately after exercise to predict endothelial dysfunction in patients with suspected coronary artery disease. Am J Cardiol 2004; 93: 10–13 [DOI] [PubMed] [Google Scholar]
  • 19. Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T, Nakanishi K: Interleukin‐18: A novel cytokine that augments both innate and acquired immunity. Adv Immunol 1998; 70: 281–312 [DOI] [PubMed] [Google Scholar]
  • 20. Whitman SC, Ravisankar P, Daugherty A: Interleukin‐18 enhances atherosclerosis in apolipoprotein E(‐/‐) mice through release of interferon‐gamma. Circ Res 2002. 8;90: E34–38 [DOI] [PubMed] [Google Scholar]
  • 21. Elhage R, Jawien J, Rudling M: Reduced atherosclerosis in interleukin‐18‐deficient apolipoprotein E‐knockout mice. Cardiovasc Res 2003; 59: 234–240 [DOI] [PubMed] [Google Scholar]
  • 22. Mallat Z, Corbaz A, Scoazec A: Interleukin‐18/interleukin‐18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 2001; 89: E41–45 [DOI] [PubMed] [Google Scholar]
  • 23. Mach F: Statins as novel immunomodulators: From cell to potential clinical benefit. Thromb Haemost 2003; 90: 607–610 [DOI] [PubMed] [Google Scholar]
  • 24. Chung HK, Lee IK, Kang H, Suh JM, Ro HK, Shong M: 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 [DOI] [PubMed] [Google Scholar]
  • 25. Tziakas DN, Chalikias GK, Parissis JT, Karas SM, Chatseras DI: Serum profiles of matrix metalloproteinases and their tissue inhibitor in patients with acute coronary syndromes: The effects of short‐term atorvastatin administration. Int J Cardiol 2004; 94: 269–277 [DOI] [PubMed] [Google Scholar]
  • 26. Albert MA, Danielson E, Rifai N, Ridker PM: Effect of statin therapy on C‐reactive protein levels: The pravastatin inflammation/CRP evaluation (PRINCE): Arandomized trial and cohort study. J Am Med Assoc 2001; 286: 64–70 [DOI] [PubMed] [Google Scholar]
  • 27. Beckman JA, Liao JK, Hurley S, Garrett LA, Chui D, Mitra D, Creager MA: Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low‐density lipoprotein. Circ Res 2004; 95: 217–223 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Tsunekawa T, Hayashi T, Kano H, Sumi D, Matsui‐Hirai H, Thakur NK, Egashira K, Iguchi A: Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2001; 104: 376–379 [DOI] [PubMed] [Google Scholar]
  • 29. Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C, and the ACCESS Study Group : Atorvastatin Comparative Cholesterol Efficacy and Safety Study. Correlation of non‐high‐density lipoprotein cholesterol with apolipoprotein B: Effect of 5‐hydroxymethylglutaryl coenzyme A reductase inhibitors on non‐high‐density lipoprotein cholesterol levels. Am J Cardiol 2001; 88 (3): 265–269 [DOI] [PubMed] [Google Scholar]

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