Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion.
Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion.
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DOI：
10.1007/s00395-019-0726-1
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发表时间：
2019-03-15
影响因子：
9.5
通讯作者：
中科院分区：
文献类型：
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我们和其他人已经报道了各种心脏病动物模型的心肌线粒体中calpain-1的增加。本研究探讨了calpain-1的组成性上调是否局限于线粒体诱导的心肌损伤和心力衰竭，如果是，是否可以通过选择性抑制线粒体超氧化物的产生来挽救这些表型。制备了心肌细胞线粒体限制性人CAPN1上调转基因小鼠（Tg-mtCapn1/tTA），其特点是线粒体限制性转基因人CAPN1低过表达和高过表达。转基因上调线粒体靶向CAPN1剂量依赖性诱导小鼠心肌细胞死亡、不良心肌重构、心力衰竭和早期死亡，这些变化与线粒体功能障碍和线粒体超氧化物的产生有关。重要的是，从2月龄开始，每天注射线粒体靶向超氧化物歧化酶模拟mito-TEMPO一个月，可减轻Tg-mtCapn1/tTA小鼠的心肌细胞死亡、不良心肌重构和心力衰竭，并降低死亡率。相比之下，给药TEMPO在转基因小鼠中没有达到类似的心脏保护作用。此外，转基因上调线粒体靶向的CAPN1诱导心脏中ATP5A1蛋白和ATP合成酶活性的降低。在体外培养的心肌细胞中，线粒体中calpain-1的升高促进了线粒体通透性过渡孔（mPTP）的开放，诱导细胞死亡，而这一过程可通过过表达ATP5A1、mito-TEMPO或mPTP开放抑制剂环孢素A来阻止。总之，本研究提供了直接证据，证明线粒体calpain-1升高是通过破坏ATP合酶、促进线粒体超氧化物生成和mPTP开放而导致心肌损伤和心力衰竭的重要机制。
We and others have reported that calpain-1 was increased in myocardial mitochondria from various animal models of heart disease. This study investigated whether constitutive up-regulation of calpain-1 restricted to mitochondria induced myocardial injury and heart failure, and if so, whether these phenotypes could be rescued by selective inhibition of mitochondrial superoxide production. Transgenic mice with human CAPN1 up-regulation restricted to mitochondria in cardiomyocytes (Tg-mtCapn1/tTA) were generated and characterized with low and high over-expression of transgenic human CAPN1 restricted to mitochondria, respectively. Transgenic up-regulation of mitochondria-targeted CAPN1 dose-dependently induced cardiac cell death, adverse myocardial remodelling, heart failure, and early death in mice, the changes of which were associated with mitochondrial dysfunction and mitochondrial superoxide generation. Importantly, a daily injection of mitochondria-targeted superoxide dismutase mimetics mito-TEMPO for one month starting from age 2 months attenuated cardiac cell death, adverse myocardial remodelling and heart failure, and reduced mortality in Tg-mtCapn1/tTA mice. In contrast, administration of TEMPO did not achieve similar cardiac protection in transgenic mice. Furthermore, transgenic up-regulation of mitochondria-targeted CAPN1 induced a reduction of ATP5A1 protein and ATP synthase activity in hearts. In cultured cardiomyocytes, increased calpain-1 in mitochondria promoted mitochondrial permeability transition pore (mPTP) opening and induced cell death, which were prevented by over-expression of ATP5A1, mito-TEMPO or cyclosporin A, an inhibitor of mPTP opening. In conclusion, this study has provided direct evidence demonstrating that increased mitochondrial calpain-1 is an important mechanism contributing to myocardial injury and heart failure by disrupting ATP synthase, and promoting mitochondrial superoxide generation and mPTP opening.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
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
作者：
Li J;Zhu H;Shen E;Wan L;Arnold JM;Peng T
通讯作者：
Peng T
影响因子：
9.7
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
通讯作者：
Rabinovitch, Peter S.
影响因子：
9.5
作者：
Gadicherla, Ashish Kumar;Wang, Nan;Leybaert, Luc
通讯作者：
Leybaert, Luc