Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age.
Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age.
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Mkk4 是与心房重塑和心律失常发生相关的转化生长因子 Beta 1 信号传导的负调节因子
DOI：
10.1161/jaha.113.000340
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发表时间：
2014-04-10
影响因子：
5.4
通讯作者：
Lei M
中科院分区：
文献类型：
--
作者：
Davies L;Jin J;Shen W;Tsui H;Shi Y;Wang Y;Zhang Y;Hao G;Wu J;Chen S;Fraser JA;Dong N;Christoffels V;Ravens U;Huang CL;Zhang H;Cartwright EJ;Wang X;Lei M
心房颤动（AF）通常与涉及调节信号介质的心脏组织的结构性纤维化变化相关，随着年龄的增长变得越来越常见。在本研究中，我们探讨了丝裂原活化蛋白激酶激酶4（Mkk 4），应激活化的丝裂原活化蛋白激酶家族的关键组成部分，在年龄相关性AF中的作用。我们开发了一种新的小鼠模型，选择性灭活心房心肌细胞Mkk 4（Mkk 4ACKO）。我们表征并比较了幼龄（3至4个月）、成年（6个月）和老龄（1岁）Mkk 4ACKO小鼠与年龄匹配的对照同窝小鼠（Mkk 4F/F）的电生理、组织学和分子特征。老龄Mkk 4ACKO小鼠比相应的Mkk 4F/F小鼠更容易发生房性快速性心律失常，表现出特征性缓慢和分散的心房传导，建模研究证明了潜在的药物效应。与Mkk 4F/F相比，这些差异导致Mkk 4ACKO中间质纤维化增加，转化生长因子β 1（TGF-β1）信号转导上调和基质金属蛋白酶失调，心房。Mkk 4失活增加了培养的心肌细胞对血管紧张素II诱导的TGF-β1信号激活的敏感性。这反过来又增强了促纤维化分子在培养的心脏成纤维细胞中的表达，表明这两种细胞类型在促纤维化信号传导中存在串扰。最后，与窦性心律的对照受试者的组织相比，AF中的人心房组织显示出与促纤维化分子产生增加相关的Mkk 4下调。这些研究结果首次证明，Mkk 4是与心房重构和随年龄发生的心房颤动相关的TGF-β1信号传导的负调节剂，确立了Mkk 4作为治疗AF的新的潜在治疗靶点。
Atrial fibrillation (AF), often associated with structural, fibrotic change in cardiac tissues involving regulatory signaling mediators, becomes increasingly common with age. In the present study, we explored the role of mitogen‐activated protein kinase kinase 4 (Mkk4), a critical component of the stress‐activated mitogen‐activated protein kinase family, in age‐associated AF. We developed a novel mouse model with a selective inactivation of atrial cardiomyocyte Mkk4 (Mkk4ACKO). We characterized and compared electrophysiological, histological, and molecular features of young (3‐ to 4‐month), adult (6‐month), and old (1‐year) Mkk4ACKO mice with age‐matched control littermates (Mkk4F/F). Aging Mkk4ACKO mice were more susceptible to atrial tachyarrhythmias than the corresponding Mkk4F/F mice, showing characteristic slow and dispersed atrial conduction, for which modeling studies demonstrated potential arrhythmic effects. These differences paralleled increased interstitial fibrosis, upregulated transforming growth factor beta 1 (TGF‐β1) signaling and dysregulation of matrix metalloproteinases in Mkk4ACKO, compared to Mkk4F/F, atria. Mkk4 inactivation increased the sensitivity of cultured cardiomyocytes to angiotensin II–induced activation of TGF‐β1 signaling. This, in turn, enhanced expression of profibrotic molecules in cultured cardiac fibroblasts, suggesting cross‐talk between these two cell types in profibrotic signaling. Finally, human atrial tissues in AF showed a Mkk4 downregulation associated with increased production of profibrotic molecules, compared to findings in tissue from control subjects in sinus rhythm. These findings together demonstrate, for the first time, that Mkk4 is a negative regulator of the TGF‐β1 signaling associated with atrial remodeling and arrhythmogenesis with age, establishing Mkk4 as a new potential therapeutic target for treating AF.