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Mechanism of induction of muscle protein degradation by angiotensin II

机译：血管紧张素Ⅱ诱导肌肉蛋白降解的机理

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Angiotensin I and II have been shown to directly induce protein degradation in skeletal muscle through an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. This investigation determines the role of the nuclear transcription factor nuclear factor-B-K (NF-B-K) in this process. Using murine myotubes as a surrogate model system both angiotensin I and II were found to induce activation of protein kinase C (PKC), with a parabolic dose-response Curve similar to the induction of total protein degradation. Activation of PKC was required for the induction of proteasome expression, since calphostin C, a highly specific inhibitor of PKC, attenuated both the increase in total protein degradation and in proteasome expression and functional activity increased by angiotensin II. PKC is known to activate I-B-K kinase (IKK), which is responsible for the phosphorylation and subsequent degradation Of I-KB. Both angiotensin I and II induced an early decrease in cytoplasmic I-B-K levels followed by nuclear accumulation of NF-KB. Using an NF-KB luciferase construct this was shown to increase transcriptional activation of NF-KB regulated genes. Maximal luciferase expression was seen at the same concentrations of angiotensin I/II as those inducing protein degradation. Total protein degradation induced by both angiotensin I and II was attenuated by resveratrol, which prevented nuclear accumulation of NF-B-K, confirming that activation of NF-KB was responsible for the increased protein degradation. These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-B-K. (c) 2005 Elsevier Inc. All rights reserved.
机译：血管紧张素I和II已显示出通过增加泛素-蛋白酶体蛋白水解途径的活性和表达直接诱导骨骼肌中的蛋白质降解。这项研究确定了核转录因子核因子-B-K（NF-B-K）在此过程中的作用。使用鼠肌管作为替代模型系统，发现血管紧张素I和II均可诱导蛋白激酶C（PKC）的激活，其抛物线剂量反应曲线类似于总蛋白降解的诱导。 PKC的激活是诱导蛋白酶体表达所必需的，因为钙磷蛋白C（一种高度特异性的PKC抑制剂）既可以减弱总蛋白降解的增加，也可以减弱血管紧张素II增强的蛋白酶体表达和功能活性。已知PKC激活I-B-K激酶（IKK），后者负责I-KB的磷酸化和随后的降解。血管紧张素I和II均诱导胞质I-B-K含量早期降低，随后NF-KB核积累。使用NF-KB萤光素酶构建体显示其增加了NF-KB调节基因的转录激活。在与诱导蛋白质降解相同的血管紧张素I / II浓度下，可以看到最大的荧光素酶表达。白藜芦醇减弱了由血管紧张素I和II诱导的总蛋白质降解，从而阻止了NF-B-K的核积累，从而证实了NF-KB的激活是蛋白质降解增加的原因。这些结果表明，通过血管紧张素I / II诱导蛋白酶体表达涉及涉及PKC和NF-B-K的信号传导途径。 （c）2005 Elsevier Inc.保留所有权利。

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