塞马3A
信号灯
肌动蛋白解聚因子
心脏纤维化
纤维化
转化生长因子
内科学
丛蛋白
心钠素
心房颤动
上皮-间质转换
心肌纤维化
西妥因1
癌症研究
医学
细胞生物学
生物
下调和上调
受体
细胞
肌动蛋白细胞骨架
遗传学
转移
细胞骨架
癌症
基因
生物化学
作者
Ying-Ju Lai,Feng-Chun Tsai,Gwo-Jyh Chang,Shang-Hung Chang,Chung-Chi Huang,Wei-Jan Chen,Yung-Hsin Yeh
摘要
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.
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