Abstract
Objective:
Activation of the endothelium by oxidized low-density lipoprotein (oxLDL) has been implicated in the development of atherosclerosis. Histone modifications impact on the transcriptional activity state of genes. We tested the hypothesis that oxLDL-induced inflammatory gene expression is regulated by histone modifications and experienced the effect of statins on these alterations.
Methods and results:
OxLDL-related interleukin-8 (IL-8) and monocyte-chemoattractant protein-1 (MCP-1) secretion in endothelial cells was reduced by statins but enhanced by histone deacetylase inhibitors. OxLDL induced lectin-like oxidized LDL receptor-1 (LOX-1) and extracellular regulated kinases (ERK1/2)-dependent acetylation of histone H3 and H4 as well as phosphorylation of histone H3, both globally and on the promoters of il8 and mcp1. Pretreatment of oxLDL-exposed cells with statins reduced the above mentioned histone modification, as well as recruitment of CREB binding protein (CBP) 300, NF-kappaB, and of RNA polymerase II but prevented loss of binding of histone deacetylase (HDAC)-1 and -2 at the il8 and mcp1 gene promoters. OxLDL reduced HDAC1 and 2 expression, and statins partly restored global HDAC-activity. Statin-related effects were reverted with mevalonate. In situ experiments indicated decreased expression of HDAC2 in endothelial cells in atherosclerotic plaques of human coronary arteries.
Conclusions:
Histone modifications seem to play an important role in atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Chemokine CCL2 / metabolism
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Coronary Vessels / enzymology
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Cytokines / genetics
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Cytokines / metabolism*
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Endothelial Cells / drug effects*
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Endothelial Cells / enzymology
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Endothelial Cells / immunology
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Fatty Acids, Monounsaturated / pharmacology
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Fluvastatin
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Gene Expression Regulation / drug effects
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Histone Deacetylase 1
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Histone Deacetylase 2
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Histone Deacetylase Inhibitors
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Histone Deacetylases / metabolism
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Histones / metabolism*
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Humans
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Hydroxamic Acids / pharmacology
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Indoles / pharmacology
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Inflammation Mediators / metabolism*
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Interleukin-8 / metabolism
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Lipoproteins, LDL / metabolism*
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Mevalonic Acid / pharmacology
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Promoter Regions, Genetic / drug effects
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RNA Interference
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RNA, Small Interfering / metabolism
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / metabolism
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Scavenger Receptors, Class E / metabolism
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Signal Transduction / drug effects
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Simvastatin / pharmacology
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Vorinostat
Substances
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CCL2 protein, human
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CXCL8 protein, human
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Chemokine CCL2
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Cytokines
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Fatty Acids, Monounsaturated
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Indoles
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Inflammation Mediators
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Interleukin-8
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Lipoproteins, LDL
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OLR1 protein, human
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RNA, Small Interfering
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Repressor Proteins
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Scavenger Receptors, Class E
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oxidized low density lipoprotein
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trichostatin A
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Fluvastatin
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Vorinostat
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Simvastatin
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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HDAC1 protein, human
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Histone Deacetylase 1
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Histone Deacetylase 2
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Histone Deacetylases
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Mevalonic Acid