Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-01-20 , DOI: 10.1007/s10565-021-09581-5 Xin Zhang 1, 2 , Can Hu 1, 2 , Yu-Pei Yuan 1, 2 , Peng Song 1, 2 , Chun-Yan Kong 1, 2 , Hai-Ming Wu 1, 2 , Si-Chi Xu 1, 2 , Zhen-Guo Ma 1, 2 , Qi-Zhu Tang 1, 2
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Cardiac endothelium communicates closely with adjacent cardiac cells by multiple cytokines and plays critical roles in regulating fibroblasts proliferation, activation, and collagen synthesis during cardiac fibrosis. E26 transformation-specific (ETS)-related gene (ERG) belongs to the ETS transcriptional factor family and is required for endothelial cells (ECs) homeostasis and cardiac development. This study aims at investigating the potential role and molecular basis of ERG in fibrotic remodeling within the adult heart. We observed that ERG was abundant in murine hearts, especially in cardiac ECs, but decreased during cardiac fibrosis. ERG knockdown within murine hearts caused spontaneously cardiac fibrosis and dysfunction, accompanied by the activation of multiple Smad-dependent and independent pathways. However, the direct silence of ERG in cardiac fibroblasts did not affect the expression of fibrotic markers. Intriguingly, ERG knockdown in human umbilical vein endothelial cells (HUVECs) promoted the secretion of endothelin-1 (ET-1), which subsequently accelerated the proliferation, phenotypic transition, and collagen synthesis of cardiac fibroblasts in a paracrine manner. Suppressing ET-1 with either a neutralizing antibody or a receptor blocker abolished ERG knockdown-mediated deleterious effect in vivo and in vitro. This pro-fibrotic effect was also negated by RGD (Arg-Gly-Asp)-peptide magnetic nanoparticles target delivery of ET-1 small interfering RNA to ECs in mice. More importantly, we proved that endothelial ERG overexpression notably prevented pressure overload-induced cardiac fibrosis. Collectively, endothelial ERG alleviates cardiac fibrosis via blocking ET-1-dependent paracrine mechanism and it functions as a candidate for treating cardiac fibrosis.
Graphical abstract
中文翻译：
内皮ERG通过阻断内皮素1依赖性旁分泌机制减轻心脏纤维化
心脏内皮通过多种细胞因子与邻近的心脏细胞紧密相连，在心脏纤维化过程中在调节成纤维细胞增殖、活化和胶原蛋白合成中起关键作用。E26 转化特异性 (ETS) 相关基因 (ERG) 属于 ETS 转录因子家族，是内皮细胞 (ECs) 稳态和心脏发育所必需的。本研究旨在调查 ERG 在成人心脏纤维化重塑中的潜在作用和分子基础。我们观察到 ERG 在小鼠心脏中含量丰富，特别是在心脏 ECs 中，但在心脏纤维化期间减少。小鼠心脏内的 ERG 敲低导致自发性心脏纤维化和功能障碍，伴随着多个 Smad 依赖性和独立途径的激活。然而，心脏成纤维细胞中 ERG 的直接沉默不影响纤维化标志物的表达。有趣的是，人脐静脉内皮细胞 (HUVECs) 中的 ERG 敲低促进了 endothelin-1 (ET-1) 的分泌，从而以旁分泌方式加速了心脏成纤维细胞的增殖、表型转变和胶原蛋白合成。用中和抗体或受体阻滞剂抑制 ET-1 在体内和体外消除了 ERG 敲低介导的有害作用。这种促纤维化作用也被 RGD（Arg-Gly-Asp）-肽磁性纳米粒子靶向递送 ET-1 小干扰 RNA 到小鼠中的 ECs 所抵消。更重要的是，我们证明了内皮 ERG 过表达显着预防了压力超负荷诱导的心脏纤维化。集体，
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