Ghrelin inhibits doxorubicin cardiotoxicity by inhibiting excessive autophagy through AMPK and p38-MAPK
Ghrelin inhibits doxorubicin cardiotoxicity by inhibiting excessive autophagy through AMPK and p38-MAPK
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Ghrelin 通过 AMPK 和 p38-MAPK 抑制过度自噬，从而抑制阿霉素心脏毒性
DOI：
10.1016/j.bcp.2014.01.040
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发表时间：
2014-04-01
影响因子：
5.8
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Wang, Xue;Wang, Xu-Lei;Jiang, Wei
多柔比星（DOX）是一种广谱抗肿瘤药物，但其心脏毒性限制了其临床应用。Ghrelin是一种多功能肽类激素，具有能量代谢调节作用，在心血管保护中发挥重要作用。目前，ghrelin对抗DOX诱导的心肌细胞凋亡和萎缩的机制尚不清楚。在本研究中，我们揭示了自噬依赖性机制参与ghrelin对DOX诱导的心肌细胞死亡和体积减小的保护作用。我们观察到DOX损伤引起小鼠显著的死亡率和心功能不全，并且在小鼠心脏和H9 c2细胞培养物中LDH漏出增加、心肌细胞凋亡以及细胞活力和体积减小，这些都被Ghrelin补充有效地改善。我们进一步观察到DOX诱导的心肌细胞自噬现象与细胞凋亡和体积缩小的程度密切相关。Ghrelin与自噬抑制剂3-MA一样，可抑制DOX诱导的心肌细胞自噬，减轻心肌细胞凋亡和体积缩小。此外，ghrelin显着降低了细胞间的氧化应激水平，一个强大的自噬触发，部分通过增加内源性抗氧化酶的表达和活性。通过进一步研究Ghrelin受体在H9 c2细胞中的后信号通路，包括ERK、p38/MAPK、JNK、AMPK和Akt，发现Ghrelin仅抑制DOX激活的AMPK，增强DOX下调的p38-MAPK和mTOR磷酸化。我们的研究结果表明，ghrelin通过抑制AMPK活性和刺激p38-MAPK活性，抑制ROS和mTOR诱导抑制过度自噬，从而有效地改善心肌细胞的存活和大小维持。(c)2014爱思唯尔公司All rights reserved.
Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by the cardiotoxicity. Ghrelin, a multi-functional peptide hormone with metabolic regulation in energy homeostasis, plays important roles in cardiovascular protection. Now, the underlying mechanisms of ghrelin against DOX-induced cardiomyocyte apoptosis and atrophy are still not clear. In the present study, we revealed an autophagy-dependent mechanism involved in ghrelin's protection against DOX-induced cardiomyocyte death and size decrease. We observed that DOX insult induced remarkable mortality and cardiac dysfunction in mice, and increase in LDH leakage, cardiomyocyte apoptosis and decrease in cell viability and size in mouse hearts and H9c2 cell cultures, which were effectively improved by ghrelin supplement. We further observed that the strong autophagy stirred by DOX exposure was paralleling with the serious apoptosis and size decrease in cardiomyocytes. Ghrelin, like an autophagy inhibitor, 3-MA, inhibited the DOX-induced autophagy and attenuated cardiomyocyte apoptosis and size decrease. Furthermore, ghrelin significantly reduced the intercellular oxidative stress level, a strong autophagy trigger, partly by augmenting the expression and activities of the endogenous anti-oxidative enzymes. After the further investigation in the post signaling pathways of ghrelin receptors in H9c2 cells, including ERK, p38/MAPK, JNK, AMPK and Akt, we observed that ghrelin supplement only reduced the DOX-activated AMPK and augmented the DOX-down regulated p38-MAPK and mTOR phosphorylation. Our results indicated that ghrelin effectively improved the cardiomyocyte survival and size maintenance by suppressing the excessive autophagy through both ROS inhibition and mTOR induction through suppressing AMPK activity and stimulating p38-MAPK activity. (c) 2014 Elsevier Inc. All rights reserved.