Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1
Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1
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表达截短的 Rho 相关卷曲螺旋蛋白激酶 1 的小鼠纤维化心肌病的机制
DOI：
10.1096/fj.11-201319
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发表时间：
2012-05-01
期刊：
影响因子：
4.8
通讯作者：
Chang, Jiang
中科院分区：
文献类型：
--
作者：
Yang, Xiangsheng;Li, Qi;Chang, Jiang
我们之前发现，在衰竭的人类心脏中，Rho相关卷曲螺旋蛋白激酶1（ROCK1）被caspase-3加工成活性亚型ROCK Delta 1。当前研究的目的是阐明截短的ROCK1在心脏中积累的病理后果、ROCK Delta 1介导的心脏表型的相关分子机制，以及心肌细胞和细胞外基质中Rho激酶激活之间的分子信号传导回应。我们培育了在心肌细胞中表达 ROCK Delta 1 的转基因小鼠，以模拟在人类心脏病中观察到的情况，同时又培育了一只缺乏激酶的小鼠作为对照。 ROCK Delta 1 转基因小鼠患上了伴有舒张功能障碍的纤维化心肌病。转基因心脏表现出激活的 TGF beta 1 和 NF-κ B 信号传导以及细胞因子子集的释放，并且对血管紧张素 II 应激敏感。 Rho 激酶抑制剂治疗减轻了纤维化表型。当与转基因心肌细胞而不是与野生型心肌细胞共培养时，心脏成纤维细胞分化为肌成纤维细胞。 Rho 激酶以及 TGF beta R1 和 NF-κ B 抑制剂可降低这些作用。血清反应因子依赖性 TGF β 1 调节被证明是 Rho 激酶介导的 TGF β 1 信号传导激活的原因。我们得出结论，ROCK Delta 1 是一种新型纤维化因子。 TGF beta 1 和 NF-κ B 信号传导的激活有助于 Rho 激酶介导的病理性纤维化。-Yang, X., Li, Q., Lin, X., Ma, Y., Yue, X., Tai, Z., Wang, F., Mckeehan, W. L., Wei, L., Schwartz, R. J., Chang, J. 表达截短基因的小鼠纤维化心肌病的机制Rho 相关卷曲螺旋蛋白激酶 1。FASEB J. 26, 2105-2116 (2012)。 www.fasebj.org
We have previously found that in failing human hearts, Rho-associated coiled-coil protein kinase 1 (ROCK1) is processed by caspase-3 into an active isoform, ROCK Delta 1. The purpose of the current investigation was to elucidate the pathological consequences of truncated ROCK1 accumulation in the heart, the associated molecular mechanism of ROCK Delta 1-mediated cardiac phenotype, and the molecular signaling between Rho kinase activation in cardiomyocytes and extracellular matrix response. We generated transgenic mice expressing ROCK Delta 1 in cardiomyocytes to mimic the situation observed in human heart disease, whereas an additional kinase-deficient mouse was generated as a control. The ROCK Delta 1 transgenic mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic hearts displayed activated TGF beta 1 and NF-kappa B signaling and a release of a subset of cytokines and were susceptible to angiotensin II stress. Treatment with a Rho kinase inhibitor attenuated the fibrotic phenotype. Cardiac fibroblasts differentiated into myofibroblasts when cocultured with transgenic cardiomyocytes but not with wild-type cardiomyocytes. Inhibitors of Rho kinase as well as TGF beta R1 and NF-kappa B decreased these effects. The serum response factor-dependent TGF beta 1 regulation was shown to be responsible for the Rho kinase-mediated activation of TGF beta 1 signaling. We conclude that ROCK Delta 1 is a novel fibrotic factor. Activation of TGF beta 1 and NF-kappa B signaling contributes to the Rho kinase-mediated pathological fibrosis.-Yang, X., Li, Q., Lin, X., Ma, Y., Yue, X., Tao, Z., Wang, F., Mckeehan, W. L., Wei, L., Schwartz, R. J., Chang, J. Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1. FASEB J. 26, 2105-2116 (2012). www.fasebj.org