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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:380.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

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

Philippe Dje N'Guessan; Fabian Riediger; Kremena Vardarova; Stefanie Scharf; Julia Eitel; Bastian Opitz; Hortense Slevogt; Wilko Weichert; Andreas C. Hocke; Bernd Schmeck; Norbert Suttorp; Stefan Hippenstiel

From the Department of Internal Medicine/Infectious Diseases and Respiratory Medicine (P.D.N., F.R., K.V., S.S., J.E., B.O., H.S., A.C.H., B.S., N.S., S.H.) and the Institute of Pathology (W.W.), Charité - Universitätsmedizin Berlin, Germany.

Correspondence to Stefan Hippenstiel, MD, Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail stefan.hippenstiel{at}charite.de

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.

Key Words: endothelium • cytokines • statins • histone • HDAC

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