Atorvastatin inhibition of cytokine‐inducible nitric oxide synthase expression in native endothelial cellsin situ
- 1 May 2002
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 136 (1) , 143-149
- https://doi.org/10.1038/sj.bjp.0704678
Abstract
Animal experimental studies have demonstrated that inducible nitric oxide synthase (iNOS) expression correlates with neointima formation and is prevented by HMG‐CoA reductase inhibitors (statins). In the present study we have investigated the underlying mechanism of action of these drugs in isolated segments of the rat aorta. Western blot analysis and immunohistochemistry revealed that tumour necrosis factor α (TNFα) plus interferon‐γ (IFNγ) synergistically induce iNOS gene expression in the endothelium but not in the smooth muscle of these segments while constitutive endothelial NO synthase (eNOS) abundance was markedly reduced. Pre‐treatment with 1 – 10 μMatorvastatin, cerivastatin or pravastatin decreased TNFα plus IFNγ stimulated iNOS expression in the endothelium irrespective of the presence of the HMG‐CoA reductase product mevalonate (400 μM). Electrophoretic mobility shift assay experiments confirmed that the combination of TNFα plus IFNγ causes activation of the transcription factors STAT‐1 and NF‐κB in native endothelial cells. Neutralization of these transcription factors by employing the corresponding decoy oligonucleotides confirmed their involvement in TNFα plus IFNγ stimulated iNOS expression. Translocation of both transcription factors was attenuated by atorvastatin, and this effect was insensitive to exogenous mevalonate. The present findings thus demonstrate a specific HMG‐CoA reductase‐independent inhibitory effect of statins, namely atorvastatin, on cytokine‐stimulated transcription factor activation in native endothelial cellsin situand the subsequent expression of a gene product implicated in vascular inflammation. This effect may be therapeutically relevant and in addition provide an explanation for the reported rapid onset of action of these drugs in humans. British Journal of Pharmacology(2002)136, 143–149; doi:10.1038/sj.bjp.0704678Keywords
This publication has 35 references indexed in Scilit:
- Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol-lowering effectsKidney International, 2000
- Direct Vascular Effects of HMG-CoA Reductase InhibitorsTrends in Cardiovascular Medicine, 2000
- Improvement of Nitric Oxide–Dependent Vasodilatation by HMG-CoA Reductase Inhibitors Through Attenuation of Endothelial Superoxide Anion FormationArteriosclerosis, Thrombosis, and Vascular Biology, 2000
- Atorvastatin reduces NF-κB activation and chemokine expression in vascular smooth muscle cells and mononuclear cellsAtherosclerosis, 1999
- Synergistic Cytokine-Induced Nitric Oxide Production in Human Alveolar Epithelial CellsNitric Oxide, 1999
- Cytokine‐inducible CD40 gene expression in vascular smooth muscle cells is mediated by nuclear factor κB and signal transducer and activato of transcription‐1FEBS Letters, 1999
- Inducible nitric oxide synthase and atherosclerosisClinical Cardiology, 1998
- Inhibition by antioxidants of nitric oxide synthase expression in murine macrophages: role of nuclear factor kB and interferon regulatory factor 1British Journal of Pharmacology, 1996
- Molecular Cloning of the Rat Inducible Nitric Oxide Synthase Gene PromoterBiochemical and Biophysical Research Communications, 1996
- Induction of L‐arginine transport and nitric oxide synthase in vascular smooth muscle cells: synergistic actions of pro‐inflammatory cytokines and bacterial lipopolysaccharideBritish Journal of Pharmacology, 1995