Mechanism of induction of muscle protein degradation by angiotensin II
Mechanism of induction of muscle protein degradation by angiotensin II
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DOI：
10.1016/j.cellsig.2005.09.009
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发表时间：
2006-07-01
影响因子：
4.8
通讯作者：
Tisdale, MJ
中科院分区：
文献类型：
--
作者：
Russell, ST;Wyke, SM;Tisdale, MJ
血管紧张素I和II已显示通过增加泛素-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。本研究确定了核转录因子核因子-B-K（NF-B-K）在这一过程中的作用。以鼠肌管为模型系统，发现血管紧张素I和II均能诱导蛋白激酶C（PKC）活化，其剂量-反应曲线呈抛物线，与诱导总蛋白降解相似。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，减弱了血管紧张素II增加的总蛋白降解和蛋白酶体表达和功能活性的增加。已知PKC激活I-B-K激酶（IKK），其负责I-KB的磷酸化和随后的降解。血管紧张素I和II均诱导细胞质I-B-K水平的早期降低，随后是NF-κ B的核积累。使用NF-κ B荧光素酶构建体，这显示出增加NF-κ B调节基因的转录激活。在与诱导蛋白质降解的浓度相同的血管紧张素I/II浓度下观察到最大荧光素酶表达。由血管紧张素I和II诱导的总蛋白质降解被白藜芦醇减弱，白藜芦醇阻止了NF-κ B的核积累，证实NF-κ B的活化是导致蛋白质降解增加的原因。这些结果表明，诱导蛋白酶体表达的血管紧张素I/II涉及一个信号通路，涉及PKC和NF-B-K。(c)2005年爱思唯尔公司All rights reserved.
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.