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 etiology. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), 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 pro-fibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 and TGF-β/Smad3 signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3; and identified the MAD homology 2 (MH2) domain of Smad3 and the coil-coil (CC) domain and DNA binding domain (DBD) of Stat3 mediated the interaction.
Conclusions: This study uncovered a previously unrecognized pro-fibrotic 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.
- Received March 24, 2017.
- Revision received July 17, 2017.
- Accepted July 24, 2017.