GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress.
GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress.
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GCN2 缺陷通过减少心肌细胞凋亡和心肌氧化应激来改善阿霉素诱导的心脏毒性。
DOI：
10.1016/j.redox.2018.04.009
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发表时间：
2018-07
期刊：
影响因子：
11.4
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Wang Y;Lei T;Yuan J;Wu Y;Shen X;Gao J;Feng W;Lu Z
阿霉素用于癌症治疗的临床应用受到其心脏毒性的限制，包括心肌细胞凋亡和氧化应激。之前，我们发现真核起始因子2α (eIF2α)激酶GCN2通过影响心肌细胞凋亡，损害心室对慢性压力过载的适应性。然而，GCN2对dox诱导的心脏毒性的影响尚未被研究。在本研究中，我们对野生型（WT）和Gcn2 - / -小鼠进行了四次腹腔注射（5 mg/kg/周）以诱导心肌病。与WT小鼠相比，经Dox治疗后，Gcn2 - / -小鼠出现更少的收缩功能障碍、心肌纤维化、细胞凋亡和氧化应激。在dox处理的小鼠心脏中，GCN2缺陷减弱了eIF2α的磷酸化，并诱导其下游靶标，激活转录因子4 （ATF4）和C/EBP同源蛋白（CHOP），并保留了抗凋亡因子Bcl-2和线粒体解偶联蛋白2（UCP2）的表达。此外，我们发现GCN2敲低减弱，而GCN2过表达加剧，dox通过eif2 α- chop依赖途径诱导细胞死亡、氧化应激和Bcl-2和UCP2表达降低。综上所述，我们的数据提供了确凿的证据，证明GCN2对Dox诱导的心肌凋亡和氧化应激有显著作用。我们的研究结果表明，抑制心肌细胞中GCN2活性的策略可能为减轻dox相关的心脏毒性提供了一种新的途径。GCN2缺乏可改善阿霉素诱导的心功能障碍。GCN2促进阿霉素诱导的心肌细胞凋亡和氧化应激。GCN2通过CHOP依赖的方式降低Bcl-2和UCP2的表达。UCP2的下调加重了阿霉素诱导的细胞死亡和氧化应激。
The clinical use of doxorubicin for cancer therapy is limited by its cardiotoxicity, which involves cardiomyocyte apoptosis and oxidative stress. Previously, we showed that general control nonderepressible 2 (GCN2), an eukaryotic initiation factor 2α (eIF2α) kinase, impairs the ventricular adaptation to chronic pressure overload by affecting cardiomyocyte apoptosis. However, the impact of GCN2 on Dox-induced cardiotoxicity has not been investigated. In the present study, we treated wild type (WT) and Gcn2−/− mice with four intraperitoneal injections (5 mg/kg/week) to induce cardiomyopathy. After Dox treatment, Gcn2−/− mice developed less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared with WT mice. In the hearts of the Dox-treated mice, GCN2 deficiency attenuated eIF2α phosphorylation and induction of its downstream targets, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and preserved the expression of anti-apoptotic factor Bcl-2 and mitochondrial uncoupling protein-2(UCP2). Furthermore, we found that GCN2 knockdown attenuated, whereas GCN2 overexpression exacerbated, Dox-induced cell death, oxidative stress and reduction of Bcl-2 and UCP2 expression through the eIF2α-CHOP-dependent pathway in H9C2 cells. Collectively, our data provide solid evidence that GCN2 has a marked effect on Dox induced myocardial apoptosis and oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in cardiomyocyte may provide a novel approach to attenuate Dox-related cardiotoxicity. GCN2 deficiency ameliorates doxorubicin-induced cardiac dysfunction. GCN2 promotes doxorubicin-induced cardiomyocyte apoptosis and oxidative stress. GCN2 decreases Bcl-2 and UCP2 expression via a CHOP dependent manner. Knockdown of UCP2 exacerbated doxorubicin-induced cell death and oxidative stress.
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影响因子：
3.4
作者：
McGowan JV;Chung R;Maulik A;Piotrowska I;Walker JM;Yellon DM
通讯作者：
Yellon DM
一般控制非阻抑性激酶 2 通过翻译后机制参与癌细胞凋亡。
影响因子：
3.3
作者：
Wei C;Lin M;Jinjun B;Su F;Dan C;Yan C;Jie Y;Jin Z;Zi-Chun H;Wu Y
通讯作者：
Wu Y
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
64.8
作者：
Costa-Mattioli, M;Gobert, D;Sonenberg, N
通讯作者：
Sonenberg, N