Statins affect the presentation of endothelial chemokines by targeting to multivesicular bodies
Open accessAbstract
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.
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Statins target chemokines to MVBs in endothelial cells.
“statins, used to reduce cholesterol level in patients and to prevent cardiovascular diseases target chemokines to MVBs in endothelial cells”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Hol et al., 2012
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Cites
Jaffe, E. A., Nachman, R., Becker, C. G., & Minick, C. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107470 · Cited by 7,146 · see citing works
PLEIOTROPIC EFFECTS OF STATINS
Liao, J. K., & Laufs, U. (2005) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095748 · Cited by 1,994 · see citing works
C hemokines in I nnate and A daptive H ost D efense : Basic Chemokinese Grammar for Immune Cells
Rot, A., & von Andrian, U. H. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104543 · Cited by 1,209 · see citing works
Weitz‐Schmidt, G., Welzenbach, K., Brinkmann, V., Kamata, T., Kallen, J. A., Bruns, C., Cottens, S., Takada, Y., & Hommel, U. (2001) · Nature Medicine · doi:10.1038/89058 · Cited by 1,041 · see citing works
A Tale of Coronary Artery Disease and Myocardial Infarction
Nabel, E. G., & Braunwald, E. (2012) · New England Journal of Medicine · doi:10.1056/nejmra1112570 · Cited by 994 · see citing works
Shitara, Y., & Sugiyama, Y. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.03.003 · Cited by 574 · see citing works
Pleiotropic Effects of Statins - Basic Research and Clinical Perspectives -
Zhou, Q., & Liao, J. K. (2010) · Circulation Journal · doi:10.1253/circj.cj-10-0110 · Cited by 567 · see citing works
Monocyte-Endothelial Cell Interactions in the Development of Atherosclerosis
Mestas, J., & Ley, K. F. (2008) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2008.11.004 · Cited by 550 · see citing works
On the preparation of cryosections for immunocytochemistry
Griffiths, G. W., McDowall, A. W., Back, R., & Dubochet, J. (1984) · Journal of Ultrastructure Research · doi:10.1016/s0022-5320(84)80024-6 · Cited by 461 · see citing works
Inflammatory mechanisms in atherosclerosis
Hansson, G. K. (2009) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2009.03416.x · Cited by 238 · see citing works
Evidence for Statin Pleiotropy in Humans
Liu, P., Liu, Y.-W., Lin, L.-J., Chen, J.-H., & Liao, J. K. (2008) · Circulation · doi:10.1161/circulationaha.108.813311 · Cited by 226 · see citing works
Neutrophil Adhesion and Activation under Flow
Zarbock, A., & Ley, K. F. (2008) · Microcirculation · doi:10.1080/10739680802350104 · Cited by 218 · see citing works
Divergent fates of P- and E-selectins after their expression on the plasma membrane.
Subramaniam, M., KOEDAM, J. A., & Wagner, D. D. (1993) · Molecular Biology of the Cell · doi:10.1091/mbc.4.8.791 · Cited by 177 · see citing works
N’Guessan, P. D., Riediger, F., Vardarova, K., Scharf, S., Eitel, J., Opitz, B., Slevogt, H., Weichert, W., Hocke, A. C., Schmeck, B., et al. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.178319 · Cited by 125 · see citing works
Rapid chemokine secretion from endothelial cells originates from 2 distinct compartments
Øynebråten, I., Bakke, O., Brandtzæg, P., et al. (2004) · Blood · doi:10.1182/blood-2003-08-2891 · Cited by 120 · see citing works
A revised model for the secretion of tPA and cytokines from cultured endothelial cells
Knipe, L., Meli, A., Hewlett, L. J., et al. (2010) · Blood · doi:10.1182/blood-2010-03-276170 · Cited by 91 · see citing works
Posvar, E. L., Radulovic, L. L., Cilla, D. D., Whitfield, L. R., & Sedman, A. J. (1996) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1996.tb04242.x · Cited by 91 · see citing works
A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis
Krüger, P., Freir, N. M., Venkatesh, B., Robertson, T. A., Roberts, M. S., & Jones, M. (2008) · Intensive Care Medicine · doi:10.1007/s00134-008-1358-3 · Cited by 87 · see citing works
Papadopoulou, C., Corrigall, V., Taylor, P. R., & Poston, R. N. (2008) · Cytokine · doi:10.1016/j.cyto.2008.05.009 · Cited by 83 · see citing works
HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size
Yamakuchi, M., Greer, J. J. M., Cameron, S. J., Matsushita, K., Morrell, C. N., Fox-Talbot, K., Baldwin, W. M., Lefer, D. J., & Lowenstein, C. J. (2005) · Circulation Research · doi:10.1161/01.res.0000170229.49776.81 · Cited by 71 · see citing works
Pleiotropic Effects and Cholesterol-Lowering Therapy
Shaw, S. M., Fildes, J. E., Yonan, N. A., & Williams, S. G. (2008) · Cardiology · doi:10.1159/000137692 · Cited by 70 · see citing works
Setiadi, H., & McEver, R. P. (2007) · Blood · doi:10.1182/blood-2007-09-113423 · Cited by 69 · see citing works
Øynebråten, I., Barois, N., Hagelsteen, K., Johansen, F., Bakke, O., & Haraldsen, G. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.8.5358 · Cited by 66 · see citing works
Self-citationA Potential Role of the CXC Chemokine GROα in Atherosclerosis and Plaque Destabilization
Breland, U. M., Halvorsen, B. L., Fosse, J. H., Øie, E., Paulsson‐Berne, G., Yndestad, A., Smith, C., Otterdal, K., Hedin, U., Wæhre, T., et al. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.162305 · Cited by 64 · see citing works
Self-citationEccles, K. A., Sowden, H., Porter, K. E., Parkin, S. M., Homer‐Vanniasinkam, S., & Graham, A. M. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.12.018 · Cited by 53 · see citing works
Schmeck, B., Beermann, W., N’Guessan, P. D., Hocke, A. C., Opitz, B., Eitel, J., Dinh, Q. T., Witzenrath, M., Krüll, M., Suttorp, N., et al. (2008) · Circulation Research · doi:10.1161/circresaha.107.161307 · Cited by 40 · see citing works
Atorvastatin affects TLR4 clustering via lipid raft modulation
Chansrichavala, P., Chantharaksri, U., Sritara, P., Kosoltanapiwat, N., & Chaiyaroj, S. C. (2010) · International Immunopharmacology · doi:10.1016/j.intimp.2010.04.027 · Cited by 40 · see citing works
Statins Inhibit Neutrophil Infiltration in Skeletal Muscle Reperfusion Injury
Cowled, P. A., Khanna, A., Laws, P. E., et al. (2007) · Journal of Surgical Research · doi:10.1016/j.jss.2006.11.021 · Cited by 37 · see citing works
Kluger, M. S., Shiao, S. L., Bothwell, A. L. M., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.5.2091 · Cited by 29 · see citing works
Fosse, J. H., Küchler, A. M., Johansen, F., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900874200 · Cited by 23 · see citing works
To JUPITER and beyond: Statins, inflammation, and primary prevention
Rao, A. D., & Milbrandt, E. B. (2010) · Critical Care · doi:10.1186/cc9006 · Cited by 13 · see citing works
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Skeletal Muscle-Released Extracellular Vesicles: State of the Art
Rome, S., Forterre, A., Mizgier, M. L., & Bouzakri, K. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00929 · Cited by 139 · see citing works
- Authors
- Hol, J., Otterdal, K., Breland, U. M., Stang, E., Pedersen, T. M., Hagelsteen, K., Ranheim, T., Kasprzycka, M., Halvorsen, B., Haraldsen, G., & Aukrust, P.
- Affiliations
- Oslo University Hospital (NO)
- Corresponding author
- Haraldsen, Guttorm
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-07-16
- Volume
- 7
- Issue
- 7
- Pages
- e40673
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3398041
- OpenAlex
- W2027428908
- Cited by
- 17
- References
- 31
- Citations by year
- 2025: 1 · 2024: 2 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 1 · 2016: 1 · 2015: 1 · 2014: 4 · 2013: 2
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Pfizer
- Norges Forskningsråd
- Helse Sør-Øst RHF
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- statins, atorvastatin, multivesicular bodies, interleukin-8, CCL2/MCP-1, E-selectin, isoprenylation, endocytic pathway, endothelial inflammation, atherosclerosis, human umbilical vein endothelial cells, IL-1β
- MeSH terms
- Atorvastatin, Fluvastatin, Cell Compartmentation, Endocytosis, Fatty Acids, Monounsaturated, Heptanoic Acids, Humans, Indoles, Pyrroles, Solubility, Subcellular Fractions, Pravastatin, Chemokines, E-Selectin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Intracellular Space, Interleukin-1beta, Chemokine CXCL1, Prenylation, Multivesicular Bodies, Tetraspanin 30, Human Umbilical Vein Endothelial Cells
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