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Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ.

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 alpha (TNFalpha) plus interferon-gamma (IFNgamma) 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 microM atorvastatin, cerivastatin or pravastatin decreased TNFalpha plus IFNgamma stimulated iNOS expression in the endothelium irrespective of the presence of the HMG-CoA reductase product mevalonate (400 microM). Electrophoretic mobility shift assay experiments confirmed that the combination of TNFalpha plus IFNgamma causes activation of the transcription factors STAT-1 and NF-kappaB in native endothelial cells. Neutralization of these transcription factors by employing the corresponding decoy oligonucleotides confirmed their involvement in TNFalpha plus IFNgamma 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 cells in situ and 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.

SUBMITTER: Wagner AH

PROVIDER: S-EPMC1762109 | biostudies-literature | 2002 May

REPOSITORIES: biostudies-literature

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Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ.

Wagner Andreas H AH Schwabe Oliver O Hecker Markus M

British journal of pharmacology 20020501 1

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 alpha (TNFalpha) plus interferon-gamma (IFNgamma) synergistically induce iNOS gene expre ...[more]

PMID: 11976279

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Project description:In rheumatoid arthritis (RA), nitric oxide (NO) is implicated in inflammation, angiogenesis and tissue destruction. The enzyme inducible nitric oxide synthase (iNOS) is responsible for the localised over-production of NO in the synovial joints affected by RA. The pro- and anti-inflammatory cytokines stimulate the synovial macrophages and the fibroblast-like synoviocytes to express iNOS. Therefore, the cytokine signalling network underlying the regulation of iNOS is essential to understand the pathophysiology of the disease. By using information from the literature, we have constructed, for the first time, the cytokine signalling network involved in the regulation of iNOS expression. Using the differential expression patterns obtained by re-analysing the microarray data on the RA synovium and the synovial macrophages available in the Gene Expression Omnibus (GEO) database, we aimed to establish the role played by the network genes towards iNOS regulation in the RA synovium. Our analysis reveals that the network genes belonging to interferon (IFN) and interleukin-10 (IL-10) pathways are always up-regulated in the RA synovium whereas the genes which are part of the anti-inflammatory transforming growth factor-beta (TGF-?) signalling pathway are mostly down-regulated. We observed a consistent up-regulation of the transcription factor signal transducers and activators of transcription 1 (STAT1) in the RA synovium and the macrophages. Interestingly, we found a consistent up-regulation of the iNOS interacting protein ras-related C3 botulinum toxin substrate 2 (RAC2) in the RA synovium as well as the macrophages. Importantly, we have constructed a model to explain the impact of IFN and IL-10 pathways on Rac2-iNOS interaction leading to over-production of NO and thereby causing chronic inflammation in the RA synovium. The interplay between STAT1 and RAC2 in the regulation of NO could have implications for the identification of therapeutic targets for RA.

Dataset Information

Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ.

Publications

Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ.

Similar Datasets

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