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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart
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MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart

机译：MAFbx / Atrogin-1对空载心脏的萎缩性重塑是必需的

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Mechanical unloading of the failing human heart induces profound cardiac changes resulting in the reversal of a distorted structure and function. In this process, cardiomyocytes break down unneeded proteins and replace those with new ones. The specificity of protein degradation via the ubiquitin proteasome system is regulated by ubiquitin ligases. Over-expressing the ubiquitin ligase MAFbx/Atrogin-1 in the heart inhibits the development of cardiac hypertrophy, but the role of MAFbx/Atrogin-1 in the unloaded heart is not known. Mechanical unloading, by heterotopic transplantation, decreased heart weight and cardiomyocyte cross-sectional area in wild type mouse hearts. Unexpectedly, MAFbx/Atrogin-1~-/- hearts hypertrophied after transplantation (n = 8-10). Proteasome activity and markers ofautophagy were increased to the same extent in WT and MAFbx/Atrogin-1~-/-hearts after transplantation (unloading). Calcineurin, a regulator of cardiac hypertrophy, was only upregulated in MAFbx/Atrogin-1~-/-transplanted hearts, while the mTOR pathway was similarly activated in unloaded WTand MAFbx/Atrogin-1~-/-hearts. MAFbx/Atrogin-1~-/- cardiomyocytes exhibited increased calcineurin protein expression, NFATtransaiptional activity, and protein synthesis rates, while inhibition of calcineurin normalized NFAT activity and protein synthesis. Lastly, mechanical unloading of failing human hearts with a left ventricular assist device (n = 18) also increased MAFbx/Atrogin-1 protein levels and expression of NFAT regulated genes. MAFbx/Atrogin-1 is required for atrophic remodeling of the heart. During unloading, MAFbx/Atrogin-1 represses calcineurin-induced cardiac hypertrophy. Therefore, MAFbx/Atrogin-1 not only regulates protein degradation, but also reduces protein synthesis, exerting a dual role in regulating cardiac mass.
机译：衰竭的人心脏的机械卸载会引起深刻的心脏变化，从而导致扭曲的结构和功能发生逆转。在这个过程中，心肌细胞分解不需要的蛋白质，并用新的蛋白质代替。通过遍在蛋白蛋白酶体系统降解蛋白质的特异性由遍在蛋白连接酶调节。心脏中过表达泛素连接酶MAFbx / Atrogin-1会抑制心脏肥大的发展，但MAFbx / Atrogin-1在空载心脏中的作用尚不清楚。通过异位移植进行的机械卸载可降低野生型小鼠心脏的体重和心肌细胞横截面积。出乎意料的是，MAFbx / Atrogin-1〜//-心脏在移植后肥大（n = 8-10）。移植（卸载）后，WT和MAFbx / Atrogin-1〜-/-心脏中的蛋白酶体活性和自噬标志物均增加了一定程度。钙调神经磷酸酶是心脏肥大的调节剂，仅在MAFbx / Atrogin-1〜-/-移植心脏中被上调，而mTOR途径在未加载的WT和MAFbx / Atrogin-1〜-/-心脏中被类似地激活。 MAFbx / Atrogin-1〜-/-心肌细胞钙调神经磷酸酶蛋白表达，NFAT转移活性和蛋白质合成速率增加，而钙调神经磷酸酶的抑制作用使NFAT活性和蛋白质合成归一化。最后，用左心室辅助装置（n = 18）对衰竭心脏进行机械卸载也增加了MAFbx / Atrogin-1蛋白水平和NFAT调控基因的表达。心脏萎缩需要MAFbx / Atrogin-1。在卸载过程中，MAFbx / Atrogin-1抑制钙调磷酸酶诱导的心脏肥大。因此，MAFbx / Atrogin-1不仅调节蛋白质降解，而且减少蛋白质合成，在调节心脏质量方面发挥双重作用。

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