EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling
EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling
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EphrinB2 通过调节 Stat3 和 TGF-β/Smad3 信号传导的相互作用来调节心脏纤维化
DOI：
10.1161/circresaha.117.311045
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发表时间：
2017-09-01
影响因子：
20.1
通讯作者：
Xiang, Meixiang
中科院分区：
文献类型：
--
作者：
Su, Sheng-an;Yang, Du;Xiang, Meixiang
原理：心脏纤维化是导致心力衰竭的左心室重塑的常见特征，无论原因如何。EphrinB 2（促红细胞生成素肝癌相互作用因子B2）是一种在哺乳动物中广泛表达的关键双向信号分子，在发育和疾病进展期间的血管生成中至关重要。最近，EphrinB 2被报道保护肾脏免受损伤诱导的纤维化。目的：探讨EphrinB 2在心肌纤维化中的作用及其在病理性重构过程中的机制。方法：EphrinB 2在晚期心力衰竭患者的心肌中高度表达，以及在心肌梗死和血管紧张素II输注诱导的心脏肥大的小鼠模型中高度表达，其伴随有肌成纤维细胞活化和胶原纤维沉积。相比之下，心肌内注射携带EphrinB 2-shRNA的慢病毒可改善心肌梗死小鼠模型的心脏纤维化并改善心脏功能。此外，在培养的心脏成纤维细胞中的体外研究表明，EphrinB 2在常氧和缺氧条件下促进心脏成纤维细胞分化为肌成纤维细胞。在机制上，通过激活Stat 3（信号转导和转录激活因子3）和TGF-β（转化生长因子-β）/Smad 3（母体抗十肢瘫痪同源物3）信号传导来确定EphrinB 2对心脏成纤维细胞的促纤维化作用。我们进一步确定EphrinB 2调节Stat 3和Smad 3之间的相互作用，并确定Smad 3的MAD同源2结构域和Stat 3的卷曲-卷曲结构域和DNA结合结构域介导了这种相互作用。这项研究揭示了EphrinB 2在心脏纤维化中先前未被认识到的促纤维化作用，这是通过Stat 3与TGF-β/Smad 3信号传导的相互作用实现的，这意味着在纤维化疾病和心力衰竭中有希望的治疗靶点。
Rationale: Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified.Objective: We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process.Methods and Results: EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-beta (transforming growth factor-beta)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil-coil domain and DNA-binding domain of Stat3 mediated the interaction.Conclusions: This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-beta/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.