Published online before print February 28, 2008, doi: 10.1161/CIRCRESAHA.107.161307
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Submitted on August 18, 2007
Revised on February 16, 2008
Accepted on February 20, 2008
Simvastatin Reduces Chlamydophila pneumoniae–Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells
Bernd Schmeck *;
From the FORSYS Junior Research Group "Systems Biology of Lung Inflammation" (B.S.), Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine (B.S., W.B., P.D.N, A.C.H., B.O., J.E., M.W., M.K., N.S., S.H.), and Department of Internal Medicine/Psychosomatic Medicine (Q.T.D.), Charité-Universitätsmedizin Berlin, Germany.
* To whom correspondence should be addressed. E-mail: bernd.schmeck{at}charite.de.
Inflammatory activation of the endothelium by Chlamydophila pneumoniae infection has been implicated in the development of chronic vascular lesions and coronary heart disease by seroepidemiological and animal studies. We tested the hypothesis that C pneumoniae induced inflammatory gene expression is regulated by Rho-GTPase–related histone modifications. C pneumoniae infection induced the liberation of proinflammatory interleukin-6, interleukin-8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1
, granulocyte/macrophage colony-stimulating factor, and interferon-
by human endothelial cells. Cytokine secretion was reduced by simvastatin and the specific Rac1 inhibitor NSC23766 but was synergistically enhanced by inhibitors of histone deacetylases trichostatin A and suberoylanilide hydroxamic acid. Infection of endothelial cells with viable C pneumoniae, but not exposure to heat-inactivated C pneumoniae or infection with C trachomatis, induced acetylation of histone H4 and phosphorylation and acetylation of histone H3. Pretreatment of C pneumoniae–infected cells with simvastatin or NSC23766 reduced global histone modifications as well as specific modifications at the il8 gene promoter, as shown by chromatin immunoprecipitation. Reduced recruitment of nuclear factor 
B p65/RelA as well as of RNA polymerase II was observed in statin-treated cells. Taken together, Rac1-mediated histone modifications seem to play an important role in C pneumoniae–induced cytokine production by human endothelial cells.
Key words: endothelial cells • cytokines • statins • Chlamydophila pneumoniae • histones
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