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首页> 外文期刊>Cellular Signalling >Mechanism of attenuation of angiotensin-II-induced protein degradation by insulin-like growth factor-I (IGF-I)
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Mechanism of attenuation of angiotensin-II-induced protein degradation by insulin-like growth factor-I (IGF-I)

机译：胰岛素样生长因子-I（IGF-I）抑制血管紧张素-II诱导的蛋白质降解的机制

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Insulin-like growth factor-I (IGF-I) has been shown to attenuate protein degradation in murine myotubes induced by angiotensin II through downregulation of the ubiquitin-proteasome pathway, although the mechanism is not known. Angiotensin II is known to upregulate this pathway through a cellular signalling mechanism involving release of arachidonic acid, activation of protein kinase C alpha (PKC alpha), degradation of inhibitor-kappa B kappa B (I-kappa KB) and nuclear migration of nuclear factor-kappa B (NF-kappa B), and all of these events were attenuated by IGF-I (13.2 nM). Induction of the ubiquitin-proteasome pathway has been linked to activation of the RNA-activated protein kinase (PKR), since an inhibitor of PKR attenuated proteasome expression and activity in response to angiotensin II and prevented the decrease in the myofibrillar protein myosin. Angiotensin II induced phosphorylation of PKR and of the eukaryotic initiation factor-2 (eIF2) on the alpha-subunit, and this was attenuated by IGF-I, by induction of the expression of protein phosphatase I, which dephosphorylates PKR. Release of arachidonic acid and activation of PKC alpha by angiotensin II were attenuated by an inhibitor of PKR and IGF-I, and the effect was reversed by Salubrinal (15 mu M), an inhibitor of eIF2 alpha dephosphorylation, as was activation of PKC alpha. In addition myotubes transfected with a dominant-negative PKR (PKR Delta 6) showed no release of arachidonate in response to Ang II, and no activation of PKC alpha. These results suggest that phosphorylation of PKR by angiotensin II was responsible for the activation of the PLA(2)/PKC pathway leading to activation of NF-kappa B and that IGF-I attenuates protein degradation due to an inhibitory effect on activation of PKR. (c) 2007 Elsevier Inc. All rights reserved.
机译：胰岛素样生长因子-I（IGF-I）已被证明可通过下调泛素-蛋白酶体途径来减轻血管紧张素II诱导的鼠肌管中的蛋白质降解，尽管其机制尚不清楚。已知血管紧张素II通过涉及花生四烯酸释放，蛋白激酶Cα（PKC alpha）活化，抑制剂-κBκB（I-κKB）降解和核因子核迁移的细胞信号传导机制上调该途径。 -κB（NF-κB），所有这些事件都被IGF-I（13.2 nM）减弱。泛素-蛋白酶体途径的诱导与RNA激活的蛋白激酶（PKR）的激活有关，因为PKR的抑制剂会减弱蛋白酶对血管紧张素II的表达和活性，并阻止肌原纤维蛋白肌球蛋白的降低。血管紧张素II诱导PKR和α亚基上的真核起始因子2（eIF2）磷酸化，并且通过诱导磷酸化磷酸酶I的蛋白磷酸酶I的表达，它被IGF-1减弱。花生四烯酸的释放和血管紧张素II对PKCα的激活被PKR和IGF-I的抑制剂减弱，而elu2α去磷酸化的抑制剂Salubrinal（15μM）则逆转了这种作用，PKCα的激活也被逆转。 。另外，用显性阴性PKR（PKR Delta 6）转染的肌管未显示响应Ang II释放花生四烯酸酯，也未激活PKCα。这些结果表明，血管紧张素II对PKR的磷酸化是PLA（2）/ PKC途径激活导致NF-κB激活的原因，而IGF-I则由于对PKR激活的抑制作用而减弱了蛋白质的降解。 （c）2007 Elsevier Inc.保留所有权利。

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