Myosin light chain phosphorylation is critical for adaptation to cardiac stress.
Myosin light chain phosphorylation is critical for adaptation to cardiac stress.
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DOI：
10.1161/circulationaha.112.116202
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发表时间：
2012-11-27
期刊：
影响因子：
37.8
通讯作者：
Kasahara H
中科院分区：
文献类型：
--
作者：
Warren SA;Briggs LE;Zeng H;Chuang J;Chang EI;Terada R;Li M;Swanson MS;Lecker SH;Willis MS;Spinale FG;Maupin-Furlowe J;McMullen JR;Moss RL;Kasahara H
心脏肥大是对循环或神经体液应激源的常见反应，是增强收缩力的机制。当心脏处于持续压力下时，肥厚反应可能演变成失代偿性心力衰竭，尽管这种转变背后的机制仍然很大程度上未知。由于心脏肌球蛋白轻链 2 (MLC2v) 的磷酸化在头杆连接处与肌球蛋白结合，促进肌动蛋白-肌球蛋白相互作用并增强收缩力，因此我们假设 MLC2v 的磷酸化在心脏对压力的适应中发挥作用。我们之前发现了一种主要磷酸化心肌细胞中 MLC2v 的酶，即 heart-MLCK (cMLCK)；然而，cMLCK 在调节健康和疾病中的心脏功能方面所发挥的作用仍有待确定。我们发现，野生型小鼠中经主动脉缩窄引起的压力过载使磷酸化 MLC2v 水平降低约 40%，cMLCK 水平降低约 85%。为了研究 cMLCK 的减少和相应的 pMLC2v 的减少如何影响功能，我们生成了 Mylk3 基因靶向小鼠以及在心肌细胞中特异性过度表达 cMLCK 的转基因小鼠。压力过载会导致 cMLCK 敲除小鼠出现严重心力衰竭，但 cMLCK 过度表达（即 cMLCK 蛋白合成超过降解）的小鼠不会出现严重心力衰竭。压力超载期间 cMLCK 蛋白的减少通过抑制泛素-蛋白酶体蛋白降解系统而减弱。我们的结果表明，泛素蛋白酶体系统加速 cMLCK 蛋白周转的新想法是由于 MLC2v 磷酸化减少而导致从代偿性肥大向失代偿性心力衰竭转变的基础。
Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac-MLCK (cMLCK); yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. We found that pressure-overload induced by transaortic constriction in wildtype mice reduced phosphorylated-MLC2v levels by ~40% and cMLCK levels by ~85%. To examine how a reduction in cMLCK and the corresponding reduction in pMLC2v affect function, we generated Mylk3 gene-targeted mice as well as transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure-overload led to severe heart failure in cMLCK knockout mice, but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure-overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. Our results suggest the novel idea that accelerated cMLCK-protein turnover by the ubiquitin-proteasome system underlie the transition from compensated hypertrophy to decompensated heart failure due to reduced phosphorylation of MLC2v.
影响因子：
3.4
作者：
Turner, Immanuel;Belema-Bedada, Fikru;Martindale, Joshua;Townsend, DeWayne;Wang, Wang;Palpant, Nathan;Yasuda, So-chiro;Barnabei, Matthew;Fomicheva, Ekaterina;Metzger, Joseph M.
通讯作者：
Metzger, Joseph M.