EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling.
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-β (transforming growth factor-β)/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-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.
['Su|Sheng-An|SA|', 'Yang|Du|D|', 'Wu|Yue|Y|', 'Xie|Yao|Y|', 'Zhu|Wei|W|', 'Cai|Zhejun|Z|', 'Shen|Jian|J|', 'Fu|Zurong|Z|', 'Wang|Yaping|Y|', 'Jia|Liangliang|L|', 'Wang|Yidong|Y|', 'Wang|Jian-An|JA|', 'Xiang|Meixiang|M|']
D000818:Animals D002478:Cells, Cultured D036388:Ephrin-B2 D005355:Fibrosis D057809:HEK293 Cells D006801:Humans D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009206:Myocardium D058628:Myofibroblasts D010100:Oxygen D050796:STAT3 Transcription Factor D015398:Signal Transduction D051900:Smad3 Protein D016212:Transforming Growth Factor beta
fibrosis myocardial infarction myofibroblasts cardiac remodeling, ventricular