Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin
Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin
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DOI：
10.1093/cvr/cvq223
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发表时间：
2010-11-01
影响因子：
10.8
通讯作者：
Zhou, Mingdong
中科院分区：
文献类型：
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作者：
Gu, Xinghua;Liu, Xifu;Zhou, Mingdong
重组人神经调节素-1（rhNRG-1）可改善实验性心力衰竭模型的心脏功能，但其潜在机制仍不清楚。本研究通过心肌肌球蛋白轻链激酶/肌球蛋白轻链2心室（myosin light chain kinase/myosin light chain 2 ventricular，cMLCK/MLC-2 v）途径，观察rhNRG-1对心肌梗死大鼠心功能的影响。用基因芯片检测非梗死心肌，探讨rhNRG-1的作用机制。通过实时荧光定量PCR、Western blot和超声心动图评估，rhNRG-1处理的动物cMLCK表达、磷酸化MLC-2 v和心功能显著上调。此外，在无血清培养的新生大鼠心肌细胞中，rhNRG-1诱导的肌节组织的恢复被cMLCK RNA干扰或MLCK抑制剂ML-7抑制。将含有大鼠cMLCK编码区的腺病毒注射到非梗死心肌中，并使用超声心动图和血液动力学机器监测心脏功能。心肌梗死后dP/dt和短轴缩短率明显降低，局部应用cMLCK后分别改善15.7%和32.1%（P均< 0.05），提示cMLCK是rhNRG-1改善心肌梗死大鼠心功能的下游效应因子，上调心肌cMLCK表达可改善心肌梗死大鼠的心功能。
Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in experimental heart failure models, but the underlying mechanism remains largely unknown. In this study, we evaluated whether rhNRG-1 could improve cardiac function via the cardiac myosin light chain kinase/myosin light chain 2 ventricular (cMLCK/MLC-2v) pathway in rats with myocardial infarction (MI).Rats with MI were intravenously infused with rhNRG-1 (5 mu g/kg/h) for 7 days through osmotic pumps. The mechanism of action of rhNRG-1 was investigated by assaying the non-infarcted myocardium with gene chips. The cMLCK expression, phosphorylated MLC-2v and cardiac function were significantly up-regulated, as assessed by real-time PCR, Western blot and echocardiography, in those animals treated with rhNRG-1. Moreover, the restoration of rhNRG-1-induced sarcomeric organization in serum-free cultured neonatal rat cardiomyocytes with rhNRG-1 was inhibited by cMLCK RNA interference or ML-7, an inhibitor of MLCKs. Adenovirus containing the rat cMLCK coding region was injected into non-infarcted myocardium, and cardiac function was monitored using echocardiography and a haemodynamic machine. The dP/dt and fractional shortening decreasing significantly after MI, and improved by 15.7 and 32.1%, respectively, following local cMLCK application (all P < 0.05).Our results suggest that cMLCK is a downstream effector of rhNRG-1 involved in rhNRG-1-induced cardiac function improvement, and that myocardial cMLCK up-regulation can improve cardiac function in rats with MI.