Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity.
Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity.
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DOI：
10.1007/s00204-019-02405-w
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发表时间：
2019-04
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
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我们最近报道，阿霉素降低了Calain-1/2的表达，而抑制Calain的活性则促进了阿霉素所致的小鼠心脏损伤。在这项研究中，我们调查了Calain-2的升高是否以及如何影响阿霉素引发的心脏损伤。获得了可诱导心肌细胞特异性表达calain-2的转基因小鼠。单次注射阿霉素(20 mg/kg)对转基因小鼠及其相应的野生型窝产仔小鼠进行急性心脏毒性实验，并于注射后5d观察心脏损伤情况。在生理条件下，心肌细胞特异性上调calain-2在3个月龄时没有诱导任何不利的心脏表型，但显著减少了阿霉素治疗的小鼠的心肌损伤并改善了心肌功能。在慢性阿霉素心脏毒性的小鼠模型中，也观察到Calain-2上调对心脏的保护作用。上调Calain-2可增加培养的小鼠心肌细胞和心脏组织中丝裂原活化蛋白激酶磷酸酶-1(MKP-1)的蛋白水平。MKP-1的过表达可阻止阿霉素诱导的心肌细胞的凋亡，而MKP-1的敲除可增强阿霉素诱导的心肌细胞的凋亡。此外，MKP-1基因敲除抵消了Calain-2对阿霉素诱导的培养心肌细胞损伤的保护作用。机制上，上调calain-2可降低磷酸酶和张力蛋白同源物的蛋白水平，从而促进Akt的激活，从而通过抑制其降解而导致MKP-1蛋白稳态水平的升高。总之，这项研究揭示了Calain-2通过磷酸酶和张力蛋白同源蛋白/Akt信号转导促进MKP-1表达的新作用。本研究还提示，Calain-2/MKP-1信号转导通路可能是阿霉素所致心脏损伤的新治疗靶点。
We recently reported that doxorubicin decreased the expression of calpain-1/2, while inhibition of calpain activity promoted doxorubicin-induced cardiac injury in mice. In this study, we investigated whether and how elevation of calpain-2 could affect doxorubicin-triggered cardiac injury. Transgenic mice with inducible cardiomyocyte-specific expression of calpain-2 were generated. An acute cardiotoxicity was induced in both transgenic mice and their relevant wild-type littermates by injection of a single dose of doxorubicin (20 mg/kg) and cardiac injury was analyzed 5 days after doxorubicin injection. Cardiomyocyte-specific up-regulation of calpain-2 did not induce any adverse cardiac phenotypes under physiological conditions by age 3 months, but significantly reduced myocardial injury and improved myocardial function in doxorubicin-treated mice. Cardiac protection of calpain-2 up-regulation was also observed in a mouse model of chronic doxorubicin cardiotoxicity. Up-regulation of calpain-2 increased the protein levels of mitogen activated protein kinase phosphatase-1 (MKP-1) in cultured mouse cardiomyocytes and heart tissues. Over-expression of MKP-1 prevented, whereas knockdown of MKP-1 augmented doxorubicin-induced apoptosis in cultured cardiomyocytes. Moreover, knockdown of MKP-1 offset calpain-2-elicited protective effects against doxorubicin-induced injury in cultured cardiomyocytes. Mechanistically, up-regulation of calpain-2 reduced the protein levels of phosphatase and tensin homolog and consequently promoted Akt activation, leading to increased MKP-1 protein steady state levels by inhibiting its degradation. Collectively, this study reveals a new role of calpain-2 in promoting MKP-1 expression via phosphatase and tensin homolog/Akt signalling. This study also suggests that calpain-2/MKP-1 signaling may represent new therapeutic targets for doxorubicin-induced cardiac injury.
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capn4 的缺失可通过防止 ATP 合酶破坏和抑制线粒体超氧化物生成来保护心脏免受内毒素损伤。
DOI：
10.1161/circheartfailure.115.002383
发表时间：
2015-09
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Ni R;Zheng D;Wang Q;Yu Y;Chen R;Sun T;Wang W;Fan GC;Greer PA;Gardiner RB;Peng T
通讯作者：
Peng T
影响因子：
7.7
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Li J;Zhu H;Shen E;Wan L;Arnold JM;Peng T
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Peng T
影响因子：
4
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Chang, Wei-Tien;Li, Jing;Haung, Hsien-Hao;Liu, Huiping;Han, Mei;Ramachandran, Srinivasan;Li, Chang-Qing;Sharp, Willard W.;Hamann, Kimm J.;Yuan, Chun-Su;Vanden Hoek, Terry L.;Shao, Zuo-Hui
通讯作者：
Shao, Zuo-Hui
影响因子：
4.8
作者：
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影响因子：
5.3
作者：
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