Involvement of Yes‐associated protein 1 (YAP1) in doxorubicin‐induced cytotoxicity in H9c2 cardiac cells
Involvement of Yes‐associated protein 1 (YAP1) in doxorubicin‐induced cytotoxicity in H9c2 cardiac cells
复制标题
Yes 相关蛋白 1 (YAP1) 参与阿霉素诱导的 H9c2 心肌细胞细胞毒性
DOI：
10.1002/cbin.11285
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发表时间：
2020
影响因子：
3.9
通讯作者：
Satoh Kumi
中科院分区：
文献类型：
--
作者：
Takaguri Akira;Akihiro Ohmiya;Sasano Jun;Satoh Kumi
心肌细胞死亡是阿霉素诱导的心脏毒性的主要事件之一，可导致心力衰竭。我们最近报道了 Yes 相关蛋白 1 (YAP1) 调节细胞存活和凋亡。然而，目前尚不清楚 YAP1 是否调节阿霉素诱导的心肌细胞细胞死亡。我们使用 H9c2 心脏细胞和小鼠心脏研究了 YAP1 是否参与阿霉素诱导的细胞死亡。在一项体内研究中，经过多柔比星治疗的小鼠心脏中 YAP1 蛋白表达显着降低，且 caspase-3 激活增加。阿霉素还通过增加 H9c2 细胞中 caspase-3 的激活而导致细胞死亡。阿霉素降低 YAP1 蛋白表达和信使 RNA 表达，同时增加 YAP1 Ser127 磷酸化。与单独使用阿霉素或 siYAP1 治疗相比，在不存在 YAP1 的情况下，阿霉素会增加 caspase-3/7 的激活，从而进一步增加细胞死亡。使用腺病毒基因转移技术过表达组成型活性 YAP1 (YAP1-5SA)，通过减少 H9c2 细胞中 caspase-3/7 的激活，显着逆转阿霉素诱导的细胞死亡。 Akt 是一种潜在的促生存因子，在阿霉素和 YAP1 短干扰 RNA (siRNA) 处理的细胞中减少。当 YAP1 沉默时，阿霉素进一步显着降低 Akt 蛋白表达。 YAP1 的过表达抵消了 H9c2 细胞中阿霉素处理诱导的 Akt 蛋白表达的降低。总之，这些结果表明阿霉素诱导的心肌细胞死亡部分是由 YAP1 和 YAP1 靶向基因 Akt 的下调介导的。调节局部心肌细胞上的 YAP1 及其相关的 Hippo 通路可能是治疗阿霉素引起的心脏毒性的一种有前途的治疗方法。
Cardiac cell death is one of the major events implicated in doxorubicin‐induced cardiotoxicity, which leads to heart failure. We recently reported that Yes‐associated protein 1 (YAP1) regulates cell survival and apoptosis. However, it is unclear whether YAP1 regulates doxorubicin‐induced cell death in cardiomyocytes. We investigated whether YAP1 is involved in doxorubicin‐induced cell death using H9c2 cardiac cells and mouse heart. In an in vivo study, YAP1 protein expression was significantly decreased in hearts of doxorubicin‐treated mice with increased caspase‐3 activation. Doxorubicin also caused cell death by increasing caspase‐3 activation in H9c2 cells. Doxorubicin reduced YAP1 protein expression and messenger RNA expression accompanied by increased phosphorylation of YAP1 at Ser127. Doxorubicin further increased cell death with increased caspase‐3/7 activation in the absence of YAP1 when compared with doxorubicin or siYAP1 treatment alone. Overexpression of constitutively active YAP1 (YAP1–5SA) using an adenovirus gene transfer technique significantly reversed doxorubicin‐induced cell death by decreasing caspase‐3/7 activation in H9c2 cells. Akt, a potential prosurvival factor, decreased in doxorubicin‐ and YAP1 short interfering RNA (siRNA)‐treated cells. Doxorubicin further significantly decreased Akt protein expression when YAP1 was silenced. Overexpression of YAP1 canceled decreased Akt protein expression induced by doxorubicin treatment in H9c2 cells. In conclusion, these results suggest that doxorubicin‐induced cardiac cell death is mediated in part by down‐regulation of YAP1 and YAP1‐targeted gene, Akt. Modulating YAP1 and its related Hippo pathway on local cardiomyocytes may be a promising therapeutic approach for doxorubicin‐induced cardiotoxicity.