Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Cellular and Molecular Biology Letters

See all formats and pricing
More options …
Volume 20, Issue 5


Cerivastatin represses atherogenic gene expression through the induction of KLF2 via isoprenoid metabolic pathways

Jiyuan Zhao
  • Corresponding author
  • School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China
  • Saint Joseph’s Translational Research Institute, Atlanta, GA, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Selvamuthu K. Natarajan / Nicolas Chronos / Jai Pal Singh
Published Online: 2016-03-05 | DOI: https://doi.org/10.1515/cmble-2015-0049


Earlier clinical studies have reported that cerivastatin has an antiatherosclerotic effect that is unique among the statins. In our study, human THP-1 macrophage cells were used to study the effects of various statins on the expressions of the atherosclerotic genes and Kruppel-like factor 2 (KLF2). Cerivastatin significantly inhibited the two atherosclerotic genes, monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor type 2 (CCR2) at both the mRNA and protein levels, while the other statins did not. Accordingly, cerivastatin was also the most potent inducer of KLF2 transcription in the macrophages. An siRNA-induced reduction in KLF2 expression blocked the inhibition of MCP-1 and CCR2 by cerivastatin. When the cells were further treated with mevalonate, farnesylpyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), the effects of cerivastatin on KLF2, MCP-1 and CCR2 were obviously reversed. Thus, the results showed that cerivastatin was a potent inhibitor of the inflammation genes MCP-1 and CCR2 through the induction of KLF2. The regulation of MCP-1, CCR2 and KLF2 by cerivastatin was isoprenoid pathway dependent. Our studies suggest that the effect of cerivastatin on atherosclerotic genes and KLF2 expression may contribute to the cardioprotection observed in reported clinical studies.

Keywords: Cerivastatin; Macrophage; Inflammation; KLF2; MCP-1; CCR2; Gene expression; Isoprenoid pathway


  • 1. Group S.S.S.S. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344 (1994) 1383-1389.Google Scholar

  • 2. Shepherd, J., Cobbe, S.M., Ford, I., Isles, C.G., Lorimer, A.R., MacFarlane P.W., McKillop, J.H. and Packard, C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333 (1995) 1301-1307.Google Scholar

  • 3. Sacks, F.M., Pfeffer, M.A., Moye, L.A., Rouleau, J.L., Rutherford, J.D., Cole, T.G., Brown, L., Warnica, J.W., Arnold, J.M., Wun, C.C., Davis, B.R. and Braunwald, E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335 (1996) 1001-1009.Google Scholar

  • 4. Group H.P.S.C. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 360 (2002) 7-22.Google Scholar

  • 5. Palinski, W. New evidence for beneficial effects of statins unrelated to lipid lowering. Arterioscler. Thromb. Vasc. Biol. 21 (2001) 3-5.CrossrefGoogle Scholar

  • 6. Wang, C.Y., Liu, P.Y. and Liao, J.K. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol. Med. 14 (2008) 37-44.Google Scholar

  • 7. Zhou, Q. and Liao, J.K. Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr. Pharm. Des. 15 (2009) 467-478.CrossrefWeb of ScienceGoogle Scholar

  • 8. Landsberger, M., Wolff, B., Jantzen, F., Rosenstengel, C., Vogelgesang, D., Staudt, A., Dahm, J.B. and Felix, S.B. Cerivastatin reduces cytokine-induced surface expression of ICAM-1 via increased shedding in human endothelial cells. Atherosclerosis 190 (2007) 43-52.Google Scholar

  • 9. Stalker, T.J., Lefer, A.M. and Scalia, R. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid. Br. J. Pharmacol. 133 (2001) 406-412.Google Scholar

  • 10. Veillard, N.R., Braunersreuther, V., Arnaud, C., Burger, F., Pelli, G., Steffens, S. and Mach, F. Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages. Atherosclerosis 188 (2006) 51-58.Google Scholar

  • 11. Achenbach, S., Ropers, D., Pohle, K., Leber, A., Thilo, C., Knez, A., Menendez, T., Maeffert, R., Kusus, M., Regenfus, M., Bickel, A., Haberl, R., Steinbeck, G., Moshage, W. and Daniel, W.G. Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation 106 (2002) 1077-1082.Google Scholar

  • 12. Raggi, P., Davidson, M., Callister, T.Q., Welty, F.K., Bachmann, G.A., Hecht, H. and Rumberger, J.A. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women: Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES). Circulation 112 (2005) 563-571.Google Scholar

  • 13. Schmermund, A., Achenbach, S., Budde, T., Buziashvili, Y., Forster, A., Friedrich, G., Henein, M., Kerkhoff, G., Knollmann, F., Kukharchuk, V., Lahiri, A., Leischik, R., Moshage, W., Schartl, M., Siffert, W., Steinhagen- Thiessen, E., Sinitsyn, V., Vogt, A., Wiedeking, B. and Erbel, R. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation 113 (2006) 427-437.Google Scholar

  • 14. Zhou, Q. and Liao, J.K. Pleiotropic effects of statins - Basic research and clinical perspectives. Circ. J. 74 (2010) 818-826.Web of ScienceGoogle Scholar

  • 15. Sen-Banerjee, S., Mir, S., Lin, Z., Hamik, A., Atkins, G.B., Das, H., Banerjee, P., Kumar, A. and Jain, M.K. Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 112 (2005) 720-726.Google Scholar

  • 16. Lin, Z., Kumar, A., SenBanerjee, S., Staniszewski, K., Parmar, K., Vaughan, D.E., Gimbrone, M.A., Balasubramanian, V., Garcia-Cardena, G. and Jain, M.K. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ. Res. 96 (2005) e48-57.Google Scholar

  • 17. Atkins, G.B., Wang, Y., Mahabeleshwar, G.H., Shi, H., Gao, H., Kawanami, D., Natesan, V., Lin, Z., Simon, D.I. and Jain, M.K. Hemizygous deficiency of Kruppel-like factor 2 augments experimental atherosclerosis. Circ. Res. 103 (2008) 690-693.Web of ScienceGoogle Scholar

  • 18. SenBanerjee, S., Lin, Z., Atkins, G.B., Greif, D.M., Rao, R.M., Kumar, A., Feinberg, M.W., Chen, Z., Simon, D.I., Luscinskas, F.W., Michel, T.M., Gimbrone, M.A., Garcia-Cardena, G. and Jain, M.K. KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. J. Exp. Med. 199 (2004) 1305-1315.Google Scholar

  • 19. Tuomisto, T.T., Lumivuori, H., Kansanen, E., Hakkinen, S.K., Turunen, M.P., van Thienen, J.V., Horrevoets, A.J., Levonen, A.L. and Yla-Herttuala, S. Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2. Cardiovasc. Res. 78 (2008) 175-184.Web of ScienceGoogle Scholar

  • 20. Winer, J., Jung, C.K., Shackel, I. and Williams, P.M. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal. Biochem. 270 (1999) 41-49.Google Scholar

  • 21. Kuijk, L.M., Mandey, S.H., Schellens, I., Waterham, H.R., Rijkers, G.T., Coffer, P.J. and Frenkel, J. Statin synergizes with LPS to induce IL-1beta release by THP-1 cells through activation of caspase-1. Mol. Immunol. 45 (2008) 2158-2165.Web of ScienceGoogle Scholar

  • 22. Shiraya, S., Miyake, T., Aoki, M., Yoshikazu, F., Ohgi, S., Nishimura, M., Ogihara, T. and Morishita, R. Inhibition of development of experimental aortic abdominal aneurysm in rat model by atorvastatin through inhibition of macrophage migration. Atherosclerosis 202 (2009) 34-40.Web of ScienceGoogle Scholar

  • 23. Tanimoto, A., Murata, Y., Wang, K.Y., Tsutsui, M., Kohno, K. and Sasaguri, Y. Monocyte chemoattractant protein-1 expression is enhanced by granulocytemacrophage colony-stimulating factor via Jak2-Stat5 signaling and inhibited by atorvastatin in human monocytic U937 cells. J. Biol. Chem. 283 (2008) 4643-4651.Web of ScienceGoogle Scholar

  • 24. Eccles, K.A., Sowden, H., Porter, K.E., Parkin, S.M., Homer-Vanniasinkam, S. and Graham, A.M. Simvastatin alters human endothelial cell adhesion molecule expression and inhibits leukocyte adhesion under flow. Atherosclerosis 200 (2008) 69-79.Google Scholar

  • 25. Bernot, D., Benoliel, A.M., Peiretti, F., Lopez, S., Bonardo, B., Bongrand, P., Juhan-Vague, I. and Nalbone, G. Effect of atorvastatin on adhesive phenotype of human endothelial cells activated by tumor necrosis factor alpha. J. Cardiovasc. Pharmacol. 41 (2003) 316-324.Google Scholar

  • 26. Kadl, A., Galkina, E. and Leitinger, N. Induction of CCR2-dependent macrophage accumulation by oxidized phospholipids in the air-pouch model of inflammation. Arthritis Rheum. 60 (2009) 1362-1371.Web of ScienceGoogle Scholar

  • 27. Carlson, C.M., Endrizzi, B.T., Wu, J., Ding, X., Weinreich, M.A., Walsh, E.R., Wani, M.A., Lingrel, J.B., Hogquist, K.A. and Jameson, S.C. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442 (2006) 299-302. Google Scholar

  • 28. Bai, A., Hu, H., Yeung, M. and Chen, J. Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription. J. Immunol. 178 (2007) 7632-7639.Web of ScienceGoogle Scholar

  • 29. Hart, G.T., Wang, X., Hogquist, K.A. and Jameson, S.C. Kruppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation, and trafficking molecule expression. Proc. Natl. Acad. Sci. USA 108 (2011) 716-721.Google Scholar

  • 30. Weis, M., Heeschen, C., Glassford, A.J. and Cooke, J.P. Statins have biphasic effects on angiogenesis. Circulation 105 (2002) 739-745.Google Scholar

  • 31. Bu, D.X., Tarrio, M., Grabie, N., Zhang, Y., Yamazaki, H., Stavrakis, G., Maganto-Garcia, E., Pepper-Cunningham, Z., Jarolim, P., Aikawa, M., Garcia-Cardena, G. and Lichtman, A.H. Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses. J. Clin. Invest. 120 (2010) 1961-1970.Web of ScienceGoogle Scholar

  • 32. Ridker, P.M. High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am. J. Cardiol. 92 (2003) 17K-22K. Google Scholar

About the article

Received: 2015-07-02

Accepted: 2015-10-22

Published Online: 2016-03-05

Published in Print: 2015-12-01

Citation Information: Cellular and Molecular Biology Letters, Volume 20, Issue 5, Pages 825–839, ISSN (Online) 1689-1392, DOI: https://doi.org/10.1515/cmble-2015-0049.

Export Citation

© University of Wroclaw, Poland.Get Permission

Comments (0)

Please log in or register to comment.
Log in