Background In addition to lowering cholesterol, statins are thought to beneficially modulate inflammation. Several chemokines including CXCL1/growth-related oncogene (GRO)-α, CXCL8/interleukin (IL)-8 and CCL2/monocyte chemoattractant protein (MCP)-1 are important in the pathogenesis of atherosclerosis and can be influenced by statin-treatment. Recently, we observed that atorvastatin-treatment alters the intracellular content and subcellular distribution of GRO-α in cultured human umbilical vein endothelial cells (HUVECs). The objective of this study was to investigate the mechanisms involved in this phenomenon. Methodology/ Principal Findings The effect of atorvastatin on secretion levels and subcellular distribution of GRO-α, IL-8 and MCP-1 in HUVECs activated by interleukin (IL)-1β were evaluated by ELISA, confocal microscopy and immunoelectron microscopy. Atorvastatin increased the intracellular contents of GRO-α, IL-8, and MCP-1 and induced colocalization with E-selectin in multivesicular bodies. This effect was prevented by adding the isoprenylation substrate GGPP, but not the cholesterol precursor squalene, indicating that atorvastatin exerts these effects by inhibiting isoprenylation rather than depleting the cells of cholesterol. Conclusions/ Significance Atorvastatin targets inflammatory chemokines to the endocytic pathway and multivesicular bodies and may contribute to explain the anti-inflammatory effect of statins at the level of endothelial cell function.
References
[1]
Nabel EG, Braunwald E (2012) A tale of coronary artery disease and myocardial infarction. The New England journal of medicine 366: 54–63.
Liu PY, Liu YW, Lin LJ, Chen JH, Liao JK (2009) Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 119: 131–138.
[4]
Zhou Q, Liao JK (2010) Pleiotropic effects of statins. - Basic research and clinical perspectives. Circulation journal : official journal of the Japanese Circulation Society 74: 818–826.
[5]
Shaw SM, Fildes JE, Yonan N, Williams SG (2009) Pleiotropic effects and cholesterol-lowering therapy. Cardiology 112: 4–12.
[6]
Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45: 89–118.
[7]
Zarbock A, Ley K (2009) Neutrophil adhesion and activation under flow. Microcirculation 16: 31–42.
[8]
Rot A, von Andrian UH (2004) Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22: 891–928.
[9]
Papadopoulou C, Corrigall V, Taylor PR, Poston RN (2008) The role of the chemokines MCP-1, GRO-alpha, IL-8 and their receptors in the adhesion of monocytic cells to human atherosclerotic plaques. Cytokine 43: 181–186.
[10]
Mestas J, Ley K (2008) Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med 18: 228–232.
[11]
Breland UM, Halvorsen B, Hol J, Oie E, Paulsson-Berne G, et al. (2008) A Potential Role of the CXC Chemokine GRO{alpha} in Atherosclerosis and Plaque Destabilization: Downregulatory Effects of Statins. Arteriosclerosis Thrombosis Vascular Biology 28: 1005–1011.
[12]
Eccles KA, Sowden H, Porter KE, Parkin SM, Homer-Vanniasinkam S, et al. (2000) Simvastatin alters human endothelial cell adhesion molecule expression and inhibits leukocyte adhesion under flow. Atherosclerosis 200: 69–79.
[13]
Yamakuchi M, Greer JJM, Cameron SJ, Matsushita K, Morrell CN, et al. (2005) HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size. Circulation Research 96: 1185–1192.
[14]
Cowled PA, Khanna A, Laws PE, Field JBF, Varelias A, et al. (2007) Statins Inhibit Neutrophil Infiltration in Skeletal Muscle Reperfusion Injury. Journal of Surgical Research 141: 267–276.
[15]
Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, et al. (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7: 687–692.
[16]
Schmeck B, Beermann W, N’Guessan PD, Hocke AC, Opitz B, et al. (2008) Simvastatin reduces Chlamydophila pneumoniae-mediated histone modifications and gene expression in cultured human endothelial cells. Circ Res 102: 888–895.
[17]
Dje N’Guessan P, Riediger F, Vardarova K, Scharf S, Eitel J, et al. (2009) Statins control oxidized LDL-mediated histone modifications and gene expression in cultured human endothelial cells. Arterioscler Thromb Vasc Biol 29: 380–386.
[18]
Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of Human Endothelial Cells Derived from Umbilical Veins. Identification by morphological and immunological criteria. J Clin Invest 52: 2745–2756.
[19]
Oynebraten I, Bakke O, Brandtzaeg P, Johansen F-E, Haraldsen G (2004) Rapid chemokine secretion from endothelial cells originates from 2 distinct compartments. Blood 104: 314–320.
[20]
Griffiths G, McDowall A, Back R, Dubochet J (1984) On the preparation of cryosections for immunocytochemistry. Journal of ultrastructure research 89: 65–78.
[21]
Hol J, Kuchler AM, Johansen FE, Dalhus B, Haraldsen G, et al. (2009) Molecular requirements for sorting of the chemokine IL-8/CXCL8 to endothelial Weibel-Palade bodies. J Biol Chem 284: 23532–23539.
[22]
Oynebraten I, Barois N, Hagelsteen K, Johansen F-E, Bakke O, et al. (2005) Characterization of a Novel Chemokine-Containing Storage Granule in Endothelial Cells: Evidence for Preferential Exocytosis Mediated by Protein Kinase A and Diacylglycerol. J Immunol 175: 5358–5369.
[23]
Knipe L, Meli A, Hewlett L, Bierings R, Dempster J, et al. (2010) A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood 116: 2183–2191.
[24]
Kluger MS, Shiao SL, Bothwell AL, Pober JS (2002) Cutting Edge: Internalization of transduced E-selectin by cultured human endothelial cells: comparison of dermal microvascular and umbilical vein cells and identification of a phosphoserine-type di-leucine motif. Journal of immunology (Baltimore, Md : 1950) 168: 2091–2095.
[25]
Setiadi H, McEver RP (2008) Clustering endothelial E-selectin in clathrin-coated pits and lipid rafts enhances leukocyte adhesion under flow. Blood 111: 1989–1998.
[26]
Subramaniam M, Koedam JA, Wagner DD (1993) Divergent fates of P- and E-selectins after their expression on the plasma membrane. Molecular biology of the cell 4: 791–801.
[27]
Chansrichavala P, Chantharaksri U, Sritara P, Ngaosuwankul N, Chaiyaroj SC (2010) Atorvastatin affects TLR4 clustering via lipid raft modulation. International Immunopharmacology 10: 892–899.
[28]
Kruger P, Freir N, Venkatesh B, Robertson T, Roberts M, et al. (2009) A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis. Intensive Care Medicine 35: 717–721.
[29]
Posvar EL, Radulovic LL, Cilla DD, Whitfield LR, Sedman AJ (1996) Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG-CoA reductase, in healthy subjects. Journal of clinical pharmacology 36: 728–731.
[30]
Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112: 71–105.
[31]
Rao AD, Milbrandt EB (2010) To JUPITER and beyond: statins, inflammation, and primary prevention. Critical care (London, England) 14: 310.
