Involvement of proteasome in endothelin-1 production in cultured vascular endothelial cells.

M. Ohkita, M. Takaoka, Yutaka Kobayashi, Eriko Itoh, Hiroko Uemachi, Y. Matsumura
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引用次数: 22

Abstract

We examined whether the proteasome could regulate endothelin (ET)-1 production in vascular endothelial cells (ECs). A proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal (PSI) significantly decreased ET-1 release from ECs by about 25% of the basal release. PSI also suppressed tumor necrosis factor (TNF)-alpha-induced ET-1 release from ECs in a dose-dependent manner. Similar inhibitory effects were observed using another proteasome inhibitor lactacystin, whereas a calpain inhibitor calpeptin had no apparent effect on ET-1 release. Furthermore, PSI significantly attenuated prepro ET-1 mRNA expression under basal and TNF-alpha-stimulated conditions. Electrophoretic mobility shift assay showed that proteasome inhibitors diminished TNF-alpha-stimulated nuclear factor-kappa B (NF-kappaB) activation in ECs. Pretreatment with antioxidants, pyrrolidine dithiocarbamate and alpha-lipoic acid, both of which are known to be suppressors of NF-kappaB activation, effectively attenuated basal and TNF-alpha-induced ET-1 release. Thus, a proteasome-dependent proteolytic pathway is at least partly involved in ET-1 production under basal conditions, and this proteolytic pathway seems to have a crucial role in ET-1 production enhanced by TNF-alpha. The reduction of NF-kappaB activation may be involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression and ET-1 release.
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蛋白酶体参与培养血管内皮细胞内皮素-1的产生。
我们研究了蛋白酶体是否可以调节血管内皮细胞(ECs)中内皮素(ET)-1的产生。蛋白酶体抑制剂N-benzyloxycarbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal (PSI)显著降低ec中ET-1的释放量,约为基础释放量的25%。PSI还以剂量依赖性的方式抑制肿瘤坏死因子(TNF)- α诱导的内皮细胞释放ET-1。另一种蛋白酶体抑制剂乳酸酵素(lactacystin)也有类似的抑制作用,而钙蛋白酶抑制剂calpain inhibitor calpeptin对ET-1释放没有明显影响。此外,在基础和tnf - α刺激条件下,PSI显著减弱了prepro ET-1 mRNA的表达。电泳迁移率转移试验表明,蛋白酶体抑制剂可降低内皮细胞中tnf - α刺激的核因子- κ B (nf - κ B)的活化。抗氧化剂,吡咯烷二硫代氨基甲酸酯和α -硫辛酸预处理,两者都是已知的NF-kappaB活化的抑制因子,有效地减弱基础和tnf - α诱导的ET-1释放。因此,在基础条件下,蛋白酶体依赖的蛋白水解途径至少部分参与了ET-1的产生,并且这种蛋白水解途径似乎在tnf - α增强的ET-1产生中起着至关重要的作用。NF-kappaB活化的降低可能与蛋白酶体抑制剂对ET-1基因转录的抑制作用以及随之而来的ET-1 mRNA表达和ET-1释放的减少有关。
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