Angiotensin II upregulates fibroblast-myofibroblast transition through Cx43-dependent CaMKII and TGF-β1 signaling in neonatal rat cardiac fibroblasts
Angiotensin II upregulates fibroblast-myofibroblast transition through Cx43-dependent CaMKII and TGF-β1 signaling in neonatal rat cardiac fibroblasts
复制标题
血管紧张素 II 通过 Cx43 依赖性 CaMKII 和 TGF-β 1 信号传导上调新生大鼠心脏成纤维细胞中成纤维细胞-肌成纤维细胞的转变
DOI：
10.1093/abbs/gmy090
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发表时间：
2018-09-01
影响因子：
3.7
通讯作者：
Yin, Yuehui
中科院分区：
文献类型：
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作者：
Cao, Li;Chen, Yunlin;Yin, Yuehui
在心脏成纤维细胞中，血管紧张素II（Ang II）可增加连接蛋白43（Cx43）表达并促进钙调素依赖性蛋白激酶II（CaMK II）活化。Cx43过表达对于成纤维细胞-肌成纤维细胞转变至关重要。本研究的主要目的是研究CaMK Ⅱ在调节Cx43表达中的作用，并确定CaMK Ⅱ/Cx43通路是否对控制成纤维细胞活化和分化至关重要。在体内，4周的血管紧张素II输注增强CaMKII激活，但减少Cx43表达的心脏经历纤维化重塑，而在培养的新生大鼠成纤维细胞，CaMKII激活上调Cx43表达通过转化生长因子β 1（TGF-β 1）。通过Ang-（1-7）或autocamtide 2相关抑制肽抑制CaMK II可逆转Ang II诱导的Cx43表达变化，并减弱Ang II诱导的α平滑肌肌动蛋白和TGF-β 1在Ang II灌注大鼠和培养成纤维细胞中的上调。基于体内和体外实验结果，CaMK II通过调节TGF-β 1和Cx43的表达在Ang II介导的成纤维细胞-肌成纤维细胞转化中起关键作用。我们得出结论，Ang II部分通过Ang II/CaMKII/TGF-β 1/Cx43信号通路介导成纤维细胞-肌成纤维细胞转变。
In cardiac fibroblasts, angiotensin II (Ang II) can increase connexin 43 (Cx43) expression and promote calmodulin-dependent protein kinase II (CaMKII) activation. Cx43 overexpression is crucial for the fibroblast-myofibroblast transition. The main purpose of the present study was to investigate the role of CaMKII in regulating Cx43 expression and to determine whether the CaMKII/Cx43 pathway is essential for controlling fibroblast activation and differentiation. In vivo, 4 weeks of Ang II infusion enhanced CaMKII activation but reduced Cx43 expression in hearts undergoing fibrosis remodeling, while in cultured neonatal rat fibroblasts, CaMKII activation upregulated Cx43 expression via transforming growth factor-betal (TGF-beta 1). CaMKII inhibition by Ang-(1-7) or autocamtide 2-related inhibitory peptide reversed the Ang II-induced changes in Cx43 expression and attenuated Ang II-induced upregulation of alpha smooth muscle actin and TGF-beta 1 in both Ang II-infused rats and cultured fibroblasts. Based on the in vivo and in vitro experimental results, CaMKII plays a pivotal role in the Ang II-mediated fibroblast-myofibroblast transition by modulating the expressions of TGF-beta 1 and Cx43. We conclude that Ang II mediates the fibroblast-myofibroblast transition partially via the Ang II/CaMKII/TGF-beta 1/Cx43 signaling pathway.