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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4188-4194. Prepublished online as a Blood First Edition Paper on February 19, 2004; DOI 10.1182/blood-2003-11-3791. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-11-3791v1 103/11/4188    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kleemann, R. Articles by Kooistra, T. Search for Related Content PubMed PubMed Citation Articles by Kleemann, R. Articles by Kooistra, T. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Evidence for anti-inflammatory activity of statins and PPAR activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro Robert Kleemann, Lars Verschuren, Bert-Jan de Rooij, Jan Lindeman, Moniek M. de Maat, Alexander J. Szalai, Hans M. G. Princen, and Teake Kooistra From the Gaubius Laboratory, Nederlandse Organisatie voor toegepast natuurwetenschappelijk onder zoek (TNO)-Prevention and Health and the Department of Vascular Surgery, Leiden University Medical Center, The Netherlands; and the Department of Medicine, University of Alabama at Birmingham. Inflammatory processes, aside from cholesterol, play a central role in atherogenesis. Human C-reactive protein (huCRP) signals systemic inflammation and independently predicts future cardiovascular risk. Cholesterol-lowering statins reduce atherosclerosis and plasma huCRP levels. Evidence is sought for a direct anti-inflammatory statin effect in vivo, independent of effects on plasma cholesterol and atherogenesis. The effect of atorvastatin and simvastatin on huCRP expression was studied in nonatherosclerotic huCRP transgenic mice and compared with another class of hypolipidemic drugs, peroxisome proliferator-activated receptor-alpha (PPAR) activators, notably fenofibrate and Wy14643. Like statins, PPAR activators combine antiatherosclerotic properties with huCRP-lowering effects. Dietary treatment with statins or PPAR activators decreased basal and interleukin-1 (IL-1)-induced plasma huCRP levels independently of cholesterol lowering. These direct anti-inflammatory in vivo effects occurred at the transcriptional level and could be confirmed in cultured human liver slices and in human hepatoma cells transiently transfected with a huCRP promoter-driven luciferase reporter. A molecular rationale for the suppression of IL-1-induced huCRP transcription is provided by showing that statins and PPAR activators up-regulate IB protein expression. This results in a reduced nuclear translocation of p50-nuclear factor B (NFB) and thereby decreased amounts of nuclear p50-NFBCCAAT/enhancer binding protein beta (C/EBP) complexes, which determine the huCRP transcription rate. Our results provide conclusive evidence for a direct suppressive effect of statins and PPAR activators on huCRP expression independent of cholesterol lowering and atherogenesis. (Blood. 2004;103:4188-4194) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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