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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction
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Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction

机译：心脏特异性MAPKKK TNNI3K的过表达促进心脏功能障碍

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Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown. We have recently shown that TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of cardiomyopathy, indicating an important role in modulating disease progression. To further investigate TNNI3K kinase activity in vivo, we have generated transgenic mice expressing both wild-type and kinase-dead versions of the human TNNI3K protein. Importantly, we show that the increased TNNI3K kinase activity induces mouse cardiac remodeling, and its kinase activity promotes accelerated disease progression in a left-ventricular pressure overload model of mouse cardiomyopathy. Using an in vitro kinase assay and proteomics analysis, we show that TNNI3K is a dual-function kinase with Tyr and Ser/Thr kinase activity. TNNI3K expression induces a series of cellular and molecular changes, including a reduction of sarcomere length and changes in titin isoform composition, which are indicative of cardiac remodeling. Using antisera to TNNI3K, we show that TNNI3K protein is located at the sarcomere Z disc. These combined data suggest that TNNI3K mediates cell signaling to modulate cardiac response to stress.
机译：心肌肌钙蛋白I相互作用激酶（TNNI3K）是一种心脏特异性激酶，其生物学功能仍然未知。我们最近显示，TNNI3K表达在心肌病小鼠模型中大大加速了心脏功能障碍，表明在调节疾病进程中具有重要作用。为进一步研究TNNI3K激酶在体内的活性，我们已经产生了表达人TNNI3K蛋白的野生型和激酶死亡版本的转基因小鼠。重要的是，我们显示增加的TNNI3K激酶活性可诱导小鼠心脏重塑，而其激酶活性可在小鼠心肌病的左心室压力超负荷模型中促进疾病的加速发展。使用体外激酶测定和蛋白质组学分析，我们显示TNNI3K是具有Tyr和Ser / Thr激酶活性的双功能激酶。 TNNI3K表达诱导一系列细胞和分子变化，包括肌节长度的减少和肌动蛋白同工型组成的变化，这表明心脏重构。使用针对TNNI3K的抗血清，我们显示TNNI3K蛋白位于肌节Z盘上。这些组合的数据表明，TNNI3K介导细胞信号传导以调节心脏对压力的反应。

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