Cerivastatin prevents tumor necrosis factor-α-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins
| Autor: | Santos Casado, Angel Celdrán, Almudena López-Blaya, L. Rico, Sandra Velasco, Antonio López-Farré, María M. Arriero, Ana Jiménez, F. González-Fernández, Jerónimo Farré |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
medicine.medical_specialty
Endothelium Pyridines Blotting Western Down-Regulation Cycloheximide chemistry.chemical_compound Cytosol Pyrrolidine dithiocarbamate Downregulation and upregulation Enos Internal medicine medicine Animals RNA Messenger Aorta Cells Cultured biology Tumor Necrosis Factor-alpha NF-kappa B Cerivastatin MRNA stabilization Blotting Northern biology.organism_classification Nitric oxide synthase medicine.anatomical_structure Endocrinology chemistry biology.protein Cattle Endothelium Vascular Hydroxymethylglutaryl-CoA Reductase Inhibitors Nitric Oxide Synthase Cardiology and Cardiovascular Medicine Protein Binding medicine.drug |
| Zdroj: | Atherosclerosis. 155:61-70 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/s0021-9150(00)00535-9 |
| Popis: | Cardiovascular disease is accompanied by an impaired endothelium-dependent vasodilatory response. Loss of endothelial nitric oxide synthase (eNOS) expression may contribute to endothelial dysfunction. The aim of the present study was to analyze the effect of cerivastatin, a novel HMG CoA reductase inhibitor, on tumor necrosis factor-alpha (TNF-alpha)-induced downregulation of eNOS protein expression in bovine aortic endothelial cells (BAEC). TNF-alpha (10 ng/ml)- incubated BAEC showed a reduced expression of eNOS protein and decreased eNOS mRNA stabilization. This effect was associated with an increased binding activity of BAEC cytosolic proteins to the 3'-untranslated region (3'UTR) of eNOS mRNA. Cerivastatin prevented TNF-alpha-induced downregulation of eNOS protein expression in a concentration-dependent manner (10(-8) to 10(-5) M). Cerivastatin also prevented the binding of the cytosolic proteins to 3'-UTR of eNOS mRNA and was associated with eNOS mRNA stabilization. The reduced expression of eNOS protein by TNF-alpha was also prevented by coincubation with cycloheximide. In addition cycloheximide inhibited the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting the inducible character of the mentioned-cytosolic proteins. TNF-alpha stimulated the translocation of nuclear factor-kappaB (NF-kappaB), an effect that was not modified by cerivastatin. Furthermore, an inhibitor of NF-kappaB translocation, pyrrolidine dithiocarbamate failed to modify both the downregulation of eNOS expression and the increased binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA by TNF-alpha. The effect of cerivastatin on eNOS expression and the binding activity of the cytosolic proteins were reversed by coincubation with L-mevalonate. In conclusion, cerivastatin stabilized eNOS mRNA and upregulated eNOS expression in the endothelium, and this was associated with a decreased binding activity of cytosolic proteins to 3'-UTR of eNOS mRNA. The effect of cerivastatin on the regulation of eNOS expression was independent of NF-kappaB mobilization by TNF-alpha. These findings suggest that cerivastatin may have beneficial effects on the endothelial dysfunction associated with cardiovascular diseases beyond its effect on lowering cholesterol. |
| Databáze: | OpenAIRE |
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