Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14-3-3γ
Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14-3-3γ
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姜黄素通过抑制氧化应激和预防 14-3-3 γ 介导的线粒体功能障碍来减轻阿霉素诱导的心脏毒性
DOI：
10.1039/c8fo00466h
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发表时间：
2018-08-01
期刊：
影响因子：
6.1
通讯作者：
He, Ming
中科院分区：
文献类型：
--
作者：
He, Huan;Luo, Yong;He, Ming
多柔比星（Dox）具有心脏毒性，限制了其在肿瘤化疗中的临床应用。心脏毒性的机制包括产生过量的细胞内ROS。已经发现14-3-3s保护心肌免受各种类型的损伤。姜黄素（Curcumin，Cur）是一种来源于姜黄的多酚类化合物，具有多种生物活性，包括抗氧化和清除自由基的活性，可发挥细胞保护作用。我们推测，Cur的心脏保护作用是通过调节14-3-3 γ发挥的。为了验证这一假设，使用Dox诱导的心脏毒性在小鼠（体内）和原代心肌细胞（体内）中建立体内心肌损伤模型。通过测定心率、心电图ST段、血清乳酸脱氢酶（LDH）和肌酸激酶（CK）活性、半胱氨酸蛋白酶3（caspase-3）活性、细胞凋亡率和心肌组织病理学改变（体内）来评价Cur的作用。此外，细胞活力，LDH，SOD，CAT，GPx和caspase-3活性，ROS，MDA和MMP水平，mPTP开放和凋亡率（体外）进行了评价。Western blot分析14-3-3 γ和Bcl-2的表达以及Bad（S112）的磷酸化水平。我们的研究结果表明，Cur通过上调心肌总蛋白中14-3-3 γ的蛋白表达和线粒体Bcl-2的表达，激活Bad（S112）磷酸化，降低心率和ST段，降低血清LDH和CK活性，从而降低caspase-3活性，降低细胞凋亡率，和心肌的组织病理学变化（体内）。此外，Dox处理增加了细胞活力和MMP水平，降低了LDH和半胱天冬酶-3活性、ROS水平、mPTP开放和凋亡率（体外）。然而，Cur的心脏保护作用被pAD/14-3-3 γ-shRNA减弱，pAD/14-3-3 γ-shRNA是一种引起细胞内14-3-3 γ表达敲低的腺病毒。总之，这是第一项证明Cur通过上调14-3-3 γ表达，从而促进Bcl-2向线粒体的易位，抑制氧化应激，改善线粒体功能，保护心肌免受Dox诱导的损伤的研究。
Doxorubicin (Dox) induces cardiotoxicity, thereby limiting its clinical application for chemotherapy of cancer. The mechanism of cardiotoxicity includes the production of excess intracellular ROS. 14-3-3s have been found to protect the myocardium against various types of injury. Curcumin (Cur) is a polyphenolic compound that is derived from turmeric and has multiple bioactivities, including anti-oxidative and radical-scavenging activities that exert cytoprotection. We hypothesize that the cardioprotective effects of Cur are exerted by regulating 14-3-3 gamma. To test the hypothesis, Dox-induced cardiotoxicity was used to establish an in vivo myocardial injury model in mice (in vivo) and primary cardiomyocytes (in intro). The effects of Cur were assessed by determining the heart rate and ECG's ST segments, as well as lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the serum, caspase-3 activity, apoptosis rate, and histopathological changes of the myocardium (in vivo). In addition, cell viability, LDH, SOD, CAT, GPx, and caspase-3 activities, levels of ROS, MDA, and MMP, mPTP opening, and the apoptosis rate (in vitro) were evaluated. The expression of 14-3-3 gamma and Bcl-2 as well as the phosphorylation levels of Bad (S112) were determined by western blot analysis. Our results showed that Dox-induced injury to the myocardium was decreased by Cur treatment via upregulating the protein expression of 14-3-3 gamma in total protein and Bcl-2 expression on mitochondria, activating Bad (S112) phosphorylation, reducing the heart rate and ST segment, and reducing LDH and CK activities in the serum, thereby causing a reduction in caspase-3 activity, the apoptosis rate, and histopathological changes of the myocardium (in vivo). Furthermore, Dox treatment increased cell viability and MMP levels, decreased LDH and caspase-3 activity, ROS levels, mPTP opening, and the apoptosis rate (in vitro). However, the cardioprotective effects of Cur were attenuated by pAD/14-3-3 gamma-shRNA, an adenovirus that caused a knock-down of intracellular 14-3-3 gamma expression. In conclusion, this is the first study to demonstrate that Cur protected the myocardium against Dox-induced injury via upregulating 14-3-3 gamma expression, thereby promoting the translocation of Bcl-2 to mitochondria, suppressing oxidative stress, and improving mitochondrial function.