Dual effects of histone deacetylase inhibition by trichostatin A on endothelial nitric oxide synthase expression in endothelial cells |
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Authors: | Gan Yehua Shen Ying H Utama Budi Wang Jian Coselli Joseph Wang Xing Li |
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Affiliation: | Laboratory of Molecular Biology and Center for TMJ Disorders, Peking University School of Stomatology, Beijing 100081, China. |
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Abstract: | Inhibition of histone deacetylases by trichostatin A (TSA) has pleiotropic effects on gene expression. We demonstrated that at low dose (0.1 microg) TSA increased the eNOS mRNA levels, which was followed by a time- and dose-dependent down-regulation. Cycloheximide, a protein synthesis inhibitor, completely abolished TSA-induced decrease in eNOS expression, indicating that new protein synthesis is required for the inhibiting effect. Mevastatin--an inhibitor HMG-CoA reductase and geranylgeranylation reaction dose-dependently antagonized TSA-induced reduction. This mevastatin-mediated antagonism was completely abolished by geranylgeranylpyrophosphate, suggesting that geranylgeranyl modification is needed to activate the eNOS mRNA destabilizing factor--a mechanism responsible for statin-mediated eNOS upregulation. |
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Keywords: | Histone deacetylase Sp1 eNOS Gene expression TSA |
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