Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway
Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway
复制标题
DOI：
10.1016/s0303-7207(03)00200-4
复制
发表时间：
2003-07-31
影响因子：
4.1
通讯作者：
Wang, PH
中科院分区：
文献类型：
--
作者：
Lai, HC;Liu, TJ;Wang, PH
胰岛素样生长因子-1 （igf1）在心肌病实验模型中抑制心肌凋亡并改善心肌功能。细胞凋亡是由线粒体功能障碍和随后的半胱天冬酶激活引发的。我们之前已经证明IGF-1通过抑制caspase抑制心肌细胞凋亡，然而，IGF-1及其信号通路如何调节心肌线粒体功能尚不清楚。在这项研究中，我们研究了igf1信号如何调节阿霉素处理的心肌细胞线粒体膜去极化。阿霉素迅速诱导线粒体电化学梯度丧失并触发原代心肌细胞线粒体去极化，而添加igf1则恢复线粒体电化学梯度。IGF - 1的作用被pi3激酶的化学抑制剂和显性负Akt阻断，表明IGF - 1向线粒体的信号通路涉及pi3激酶-Akt通路。用组成型活性PI 3激酶转导心肌细胞部分恢复阿霉素处理细胞的线粒体电化学梯度。这些发现为igf1调节线粒体功能是通过激活pi3激酶和Akt介导的提供了直接证据。另外使用线粒体K-ATP通道激动剂和拮抗剂的实验表明，igf1信号传递到线粒体膜并不直接涉及K-ATP通道。这些发现表明，细胞质信号传导至线粒体可能在阿霉素的心脏毒性作用和IGF - 1的心脏保护作用中发挥了重要作用。2003爱思唯尔爱尔兰有限公司版权所有。
Insulin-like growth factor-1 (IGF 1) suppresses myocardial apoptosis and improves myocardial function in experimental models of cardiomyopathy. Apoptosis is triggered by mitochondria dysfunction and subsequent activation of caspases. We had previously shown that IGF 1 inhibited cardiomyocyte apoptosis via suppression of caspase, however, how IGF-1 and its signaling pathway modulates mitochondria function in cardiac muscle is not yet known. In this study we investigated how IGF 1 signaling modulates mitochondria membrane depolarization in the cardiomyocytes treated with doxorubicin. Doxorubicin rapidly induced loss of mitochondria electrochemical gradient and triggered mitochondria depolarization in primary cardiomyocytes, whereas addition of IGF 1 restored mitochondria electrochemical gradient. The effects of IGF 1 was blocked by a chemical inhibitor of PI 3 kinase and a dominant negative Akt, suggesting that IGF 1 signaling to mitochondria involves the PI 3 kinase-Akt pathway. Transducing cardiomyocytes with constitutive active PI 3 kinase partially restored the mitochondria electrochemical gradient in doxorubicin-treated cells. These findings provide direct evidence that IGF 1 modulation of mitochondria, function is mediated through activation of PI 3 kinase and Akt. Additional experiments using agonist and antagonist of mitochondria K-ATP channel suggest that IGF 1 signaling to mitochondria membrane does not directly involve K-ATP channel. These findings suggest that cytosolic signaling to mitochondria may play a fundamental role in the cardiotoxic actions of doxorubicin and cardioprotective actions of IGF 1. (C) 2003 Elsevier Ireland Ltd. All rights reserved.