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Simvastatin abrogates inflamed neutrophil adhesive properties, in association with the inhibition of Mac-1 integrin expression and modulation of Rho kinase activity

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Abstract

Objectives

Leukocytes play a primary role in vascular inflammation, and thus an understanding of the pathways involved in the activation of these cells and means to inhibit their consequent adhesion to the vessel wall is of significant interest. This study aimed to determine whether statins have a direct effect upon neutrophil adhesive properties under inflammatory conditions.

Methods

Neutrophils from healthy individuals were subjected to adhesion assays (with fibronectin as ligand) and flow cytometry.

Results

In the presence of a TNF-α inflammatory stimulus, neutrophils displayed a rapid and substantial enhancement in their adhesive properties that was abrogated by preincubation of cells with simvastatin. Neutrophil surface expression of the Mac-1 integrin subunit, CD11b, was augmented by TNF-α, and this increased expression was also inhibited by simvastatin. TNF-α also induced neutrophil LFA-1 and Mac-1 activation, but this activation was not blocked by simvastatin. Interestingly, while addition of the isoprenoids, geranygerayl pyrophosphate and farnesyl pyrophosphate, to cells did not alter the effect of simvastatin on TNF-α-stimulated adhesion, concurrent incubation of cells with the Rho kinase (ROCK) inhibitor reversed the effects of simvastatin on neutrophil adhesion and CD11b expression.

Conclusion

Simvastatin appears to have direct anti-inflammatory effects in neutrophils that may be mediated by modulation of ROCK activity.

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References

  1. Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res. 2012;110:875–88.

    Article  PubMed  CAS  Google Scholar 

  2. Conran N, Franco-Penteado CF, Costa FF. Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. Hemoglobin. 2009;33:1–16.

    Article  PubMed  CAS  Google Scholar 

  3. Chesnutt BC, Smith DF, Raffler NA, Smith ML, White EJ, Ley K. Induction of LFA-1-dependent neutrophil rolling on ICAM-1 by engagement of E-selectin. Microcirculation. 2006;13:99–109.

    Article  PubMed  CAS  Google Scholar 

  4. Mihos CG, Salas MJ, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. Cardiol Rev. 2010;18:298–304.

    Article  PubMed  Google Scholar 

  5. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5:378–87.

    Article  PubMed  CAS  Google Scholar 

  6. Huveneers S, Danen EH. Adhesion signaling—crosstalk between integrins Src and Rho. J Cell Sci. 2009;122:1059–69.

    Article  PubMed  CAS  Google Scholar 

  7. Eccles KA, Sowden H, Porter KE, Parkin SM, Homer-Vanniasinkam S, Graham AM. Simvastatin alters human endothelial cell adhesion molecule expression and inhibits leukocyte adhesion under flow. Atherosclerosis. 2008;200:69–79.

    Article  PubMed  CAS  Google Scholar 

  8. Canalli AA, Proenca RF, Franco-Penteado CF, Traina F, Sakamoto TM, Saad ST, et al. Participation of Mac-1, LFA-1 and VLA-4 integrins in the in vitro adhesion of sickle cell disease neutrophils to endothelial layers, and reversal of adhesion by simvastatin. Haematologica. 2011;96:526–33.

    Article  PubMed  CAS  Google Scholar 

  9. Assis A, Conran N, Canalli AA, Lorand-Metze I, Saad ST, Costa FF. Effect of cytokines and chemokines on sickle neutrophil adhesion to fibronectin. Acta Haematol. 2005;113:130–6.

    Article  PubMed  CAS  Google Scholar 

  10. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982;78:206–9.

    Article  PubMed  CAS  Google Scholar 

  11. Najib NM, Idkaidek N, Adel A, Admour I, Astigarraga RE, Nucci GD, et al. Pharmacokinetics and bioequivalence evaluation of two simvastatin 40 mg tablets (Simvast and Zocor) in healthy human volunteers. Biopharm Drug Dispos. 2003;24:183–9.

    Article  PubMed  CAS  Google Scholar 

  12. Choi M, Rolle S, Rane M, Haller H, Luft FC, Kettritz R. Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA. Kidney Int. 2003;63:96–106.

    Article  PubMed  CAS  Google Scholar 

  13. Yang JC, Huang F, Wu CJ, Chen YC, Lu TH, Hsieh CH. Simvastatin reduces VCAM-1 expression in human umbilical vein endothelial cells exposed to lipopolysaccharide. Inflamm Res. 2012;61:485–91.

    Article  PubMed  CAS  Google Scholar 

  14. Kaneider NC, Egger P, Dunzendorfer S, Wiedermann CJ. Rho-GTPase-dependent platelet-neutrophil interaction affected by HMG-CoA reductase inhibition with altered adenosine nucleotide release and function. Arterioscler Thromb Vasc Biol. 2002;22:1029–35.

    Article  PubMed  CAS  Google Scholar 

  15. Walter T, Suselbeck T, Borggrefe M, Swoboda S, Hoffmeister HM, Dempfle CE. Effect of atorvastatin on cellular adhesion molecules on leukocytes in patients with normocholesterolemic coronary artery disease. In Vivo. 2010;24:189–93.

    PubMed  CAS  Google Scholar 

  16. Smalley DM, Ley K. L-selectin: mechanisms and physiological significance of ectodomain cleavage. J Cell Mol Med. 2005;9:255–66.

    Article  PubMed  CAS  Google Scholar 

  17. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001;7:687–92.

    Article  PubMed  CAS  Google Scholar 

  18. Weitz-Schmidt G, Welzenbach K, Dawson J, Kallen J. Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by X-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo. J Biol Chem. 2004;279:46764–71.

    Article  PubMed  CAS  Google Scholar 

  19. Maher BM, Dhonnchu TN, Burke JP, Soo A, Wood AE, Watson RW. Statins alter neutrophil migration by modulating cellular Rho activity—a potential mechanism for statins-mediated pleotropic effects? J Leukoc Biol. 2009;85:186–93.

    Article  PubMed  CAS  Google Scholar 

  20. Xiao Y, Liang L, Pan Y, Lian F, Li L, Lin H, et al. Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA. Rheumatol Int 2012. doi:10.1007/s00296-012-2383-7

  21. Xenos ES, Stevens SL, Freeman MB, Cassada DC, Goldman MH. Nitric oxide mediates the effect of fluvastatin on intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression on human endothelial cells. Ann Vasc Surg. 2005;19:386–92.

    Article  PubMed  Google Scholar 

  22. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97:1129–35.

    Article  PubMed  CAS  Google Scholar 

  23. Li XD, Yang YJ, Geng YJ, Zhao JL, Zhang HT, Cheng YT, et al. Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway. Acta Pharmacol Sin. 2012;33:879–87.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by research funds from Fundacão de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and CNPq, Brazil. The Hematology and Hemotherapy Center, UNICAMP, forms part of the National Institute of Blood, Brazil (INCT de Sangue, CNPq/MCT/FAPESP). The authors would like to thank Ana Leda Longhini and Irene Santos for flow cytometry analysis.

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Correspondence to Nicola Conran.

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Responsible editor: Graham Wallace.

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Silveira, A.A.A., Dominical, V.M., Lazarini, M. et al. Simvastatin abrogates inflamed neutrophil adhesive properties, in association with the inhibition of Mac-1 integrin expression and modulation of Rho kinase activity. Inflamm. Res. 62, 127–132 (2013). https://doi.org/10.1007/s00011-012-0579-7

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  • DOI: https://doi.org/10.1007/s00011-012-0579-7

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