Statins Control Oxidized LDL-Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells

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-B, 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. (Arterioscler Thromb Vasc Biol.2009;29:380-386.)Key Words: endothelium Ⅲ cytokines Ⅲ statins Ⅲ histone Ⅲ HDAC A therosclerosis is a chronic inflammatory disease of the arterial wall. Increased oxLDL serum levels are considered as an important risk factor for atherosclerosis, 1,2 and oxLDL accumulation in the vessel wall has been suggested to trigger endothelial inflammation. 1 Expression of cyto-and chemokines and adhesion molecules by activated endothelium promotes monocyte/lymphocyte infiltration into the subendothelium thus stimulating inflammation of the vessel wall. 2 In particular, strong chemoattractants and proinflammatory cytokines like IL-8 and MCP-1 liberated by inflamed endothelium contribute to leukocyte attraction 2 in atherosclerosis. 3,4 LOX-1 is increasingly linked to atherosclerotic plaque formation. 5 LOX-1 activation by oxLDL stimulates endothelial proinflammatory gene expression and production of superoxide radicals. 5 Increasing evidence indicates that histone modifications are important for the transcriptional activity state of genes in many cellular processes. In chromatin, 146 base pairs of DNA are wrapped 1.65 turns around a histone octamer (H2A, H2B, H3, H4). 6 Transcription repression or gene activation is regulated by specific covalent modifications of accessible N-terminal histone tails 7,8 including acetylation (mostly lysine) and phosphorylation (serine/threonine). 9 For example, histone acetylases (HATs) increase histone acetylation thereby reducing DNA-histone binding and facilitating gene transcription whereas histo...

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