Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress
Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress
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DOI：
10.1016/j.yjmcc.2012.11.006
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发表时间：
2013-01-01
影响因子：
5
通讯作者：
Christensen, Geir
中科院分区：
文献类型：
--
作者：
Herum, Kate M.;Lunde, Ida G.;Christensen, Geir
压力过载激活心脏成纤维细胞，导致过度生产细胞外基质，这可能有助于心功能受损。活化的成纤维细胞获得平滑肌样特征，如表达平滑肌α -肌动蛋白（SMA）和SM22，因此被称为肌成纤维细胞。机械应力诱导的肌成纤维细胞分化的分子机制尚不明确。本研究的目的是研究跨膜蛋白多糖syndecan-4和活化t细胞的钙调磷酸酶依赖转录因子核因子（NFAT）在肌成纤维细胞分化中的潜在作用。主动脉束带导致野生型小鼠左心室胶原- land III、纤维连接蛋白、SMA和SM22 mRNA升高，而在syndecan-4（-/-）小鼠中，这种反应明显减弱。肌成纤维细胞的体外分化与SMA、胶原I和III表达以及NFAT-荧光素酶活性的增加有关，在syndecan-4（-/-）小鼠或钙调磷酸酶/NFAT阻滞剂治疗后，所有这些在成纤维细胞中都降低了。循环拉伸后，NFATc4在心脏成纤维细胞中以syndecan-4和钙调磷酸酶依赖的方式被激活。Syndecan-4和钙调神经磷酸酶共定位和机械应力导致Syndecan-4丝氨酸179的去磷酸化，这是钙调神经磷酸酶相互作用的关键细胞内残基。NFATc4的过表达上调了III型胶原蛋白、MRTF-A （SMA的转录调节因子）和nfat靶钙调磷酸酶1.4 （RCAN1.4）。我们的数据表明，在压力过载的心脏中，syndecan-4对于心脏成纤维细胞向肌成纤维细胞的分化是重要的，并且钙调磷酸酶/NFAT通路以syndecan-4依赖的方式参与机械应力，在肌成纤维细胞分化和细胞外基质的产生中发挥积极作用。这篇文章是题为“可能的社论”的特刊的一部分。(c) 2012 Elsevier Ltd.版权所有。
Pressure overload activates cardiac fibroblasts leading to excessive production of extracellular matrix which may contribute to compromised heart function. The activated fibroblast acquires smooth muscle-like features such as expression of smooth muscle alpha-actin (SMA) and SM22 and is therefore referred to as myofibroblast. The molecular mechanisms underlying mechanical stress-induced myofibroblast differentiation are poorly defined. The objective of this study was to examine the potential roles of the transmembrane proteoglycan syndecan-4 and the calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in myofibroblast differentiation. Aortic banding resulted in elevated collagen land III, fibronectin, SMA and SM22 mRNA in the left ventricles of wild-type mice, whereas this response was markedly reduced in syndecan-4(-/-) mice. Myofibroblast differentiation in vitro was associated with increased SMA, collagen I and III expression and NFAT-luciferase activity, all of which were reduced in fibroblasts from syndecan-4(-/-) mice or after treatment with calcineurin/NFAT blockers. Following cyclic stretch, NFATc4 was activated in cardiac fibroblasts in a syndecan-4- and calcineurin-dependent manner. Syndecan-4 and calcineurin co-localized and mechanical stress resulted in dephosphorylation of serine179 of syndecan-4, an intracellular residue critical for calcineurin interaction. Over-expression of NFATc4 up-regulated collagen III, MRTF-A (a transcriptional regulator of SMA) and the NFAT-target regulator of calcineurin 1.4 (RCAN1.4). Our data demonstrate that syndecan-4 is important for the differentiation of cardiac fibroblasts into myofibroblasts in the pressure-overloaded heart and that the calcineurin/NFAT pathway is engaged upon mechanical stress in a syndecan-4-dependent manner, playing an active role in myofibroblast differentiation and extracellular matrix production. This article is part of a Special Issue entitled 'Possible Editorial'. (c) 2012 Elsevier Ltd. All rights reserved.