EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling

Su, Sheng-an; Du, Yang; Wu, Yue; Xie, Yao; Zhu, Wei; Cai, Zhejun; Shen, Jian; Fu, Zurong; Wang, Yaping; Liu, Jia; Wang, Yidong; Wang, Jianan; Xiang, Meixiang

doi:10.1161/circresaha.117.311045

Cited by 118 publications

(66 citation statements)

References 27 publications

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“…This reversal of the fibrotic response to radiotherapy is accompanied by a significant reduction in circulating IL17 in the PANC272 model, a proinflammatory cytokine shown to participate in fibrosis formation (58). Our findings are supported by a cardiac fibrosis model, where it was shown that EFNB2 activates Stat3 and TGFb/Smad3 signaling to induce cardiac fibrogenesis (40), and lung and skin fibrosis models, where soluble EFNB2 promotes fibroblast chemotaxis and activation (41).…”

Section: Discussionsupporting

confidence: 68%

“…High levels of expression of collagens Col1a2, Col2a1, and Col4a1 have been shown to associate with lower overall survival in patients with PDAC (70). In a cardiac fibrosis model, it was shown that EFNB2 activates Stat3 and TGFb/ Smad3 signaling to induce cardiac fibrogenesis (40), and in lung and skin fibrosis models, it was shown that soluble EFNB2 promotes fibroblast chemotaxis and activation (41). EFNB2 is known to be a regulator of TGFb1 signaling, and it has been shown that mice injected with lentivirus EFNB2 shRNA produce less active TGFb1 than control plasmid-injected mice (40).…”

Section: Discussionmentioning

confidence: 99%

“…Blockade of EphB4-ephrin-B2 signaling with B11 and depletion of Tregs decreases fibrosis PDAC-associated fibrosis has been viewed as a physical barrier that compromises drug delivery, reduces immune cell accessibility, and promotes disease aggression and therapy resistance (57). More recently, EFNB2 has been shown to be a critical regulator of fibrosis in other model systems (40,41). We therefore tested the effect of EphB4-EFNB2 inhibition with and without radiotherapy on fibrosis.…”

Section: Depletion Of Tregs Combined With Radiotherapy Controls Tumormentioning

confidence: 99%

“…This interaction regulates multiple oncogenic processes, including angiogenesis, lymphangiogenesis, hematopoietic cell trafficking, and T-cell proliferation and activation (32)(33)(34)(35)(36)(37)(38)(39). More recently, in noncancer models of cardiac, skin, and lung injury, EFNB2-EphB4 interaction has also been shown to be a key regulator of fibrosis (40,41).…”

Section: Introductionmentioning

confidence: 99%

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Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination

Lennon

Oweida

Milner

et al. 2019

Clinical Cancer Research

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Purpose: A driving factor in pancreatic ductal adenocarcinoma (PDAC) treatment resistance is the tumor microenvironment, which is highly immunosuppressive. One potent immunologic adjuvant is radiotherapy. Radiation, however, has also been shown to induce immunosuppressive factors, which can contribute to tumor progression and formation of fibrotic tumor stroma. To capitalize on the immunogenic effects of radiation and obtain a durable tumor response, radiation must be rationally combined with targeted therapies to mitigate the influx of immunosuppressive cells and fibrosis. One such target is ephrinB2, which is overexpressed in PDAC and correlates negatively with prognosis. Experimental Design: On the basis of previous studies of ephrinB2 ligand-EphB4 receptor signaling, we hypothesized that inhibition of ephrinB2-EphB4 combined with radiation can regulate the microenvironment response postradiation, leading to increased tumor control in PDAC. This hypothesis was explored using both cell lines and in vivo human and mouse tumor models. Results: Our data show this treatment regimen significantly reduces regulatory T-cell, macrophage, and neutrophil infiltration and stromal fibrosis, enhances effector T-cell activation, and decreases tumor growth. Furthermore, our data show that depletion of regulatory T cells in combination with radiation reduces tumor growth and fibrosis. Conclusions: These are the first findings to suggest that in PDAC, ephrinB2-EphB4 interaction has a profibrotic, protumorigenic role, presenting a novel and promising therapeutic target.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Depletion Of Tregs Combined With Radiotherapy Controls Tumormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination

Lennon

Oweida

Milner

et al. 2019

Clinical Cancer Research

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“…A shedding of ephrinB2 into the alveolar space has been shown to occur during myofibroblast activation and lung fibrosis . Additionally, ephrinB2 has been implicated in cardiac fibrosis and increased endothelial adhesion molecule expression . The increased ephrinB2 levels indicate an increased ephrinB2 shedding, which could happen not only in pulmonary but also in systemic vessels.…”

Section: Discussionmentioning

confidence: 99%

Retrograde perfusion in isolated perfused mouse lungs—Feasibility and effects on cytokine levels and pulmonary oedema formation

Krabbe

Ruske

Kanzler

et al. 2019

Basic Clin Pharma Tox

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Retrograde lung vascular perfusion can appear in high‐risk surgeries. The present report is the first to study long‐term retrograde perfusion of isolated perfused mouse lungs (IPLs) and to use the tyrosine kinase ephB4 and its ligand ephrinB2 as potential markers for acute lung injury. Mouse lungs were subjected to anterograde or retrograde perfusion with normal‐pressure ventilation (NV) or high‐pressure ventilation (=overventilation, OV) for 4 hours. Outcome parameters were cytokine, ephrinB2 and ephB4 levels in perfusate samples and bronchoalveolar lavage (BAL), and the wet‐to‐dry ratio. Anterograde perfusion was feasible for 4 hours, while lungs receiving retrograde perfusion presented considerable collapse rates. Retrograde perfusion resulted in an increased wet‐to‐dry ratio when combined with high‐pressure ventilation; other physiological parameters were not affected. Cytokine levels in BAL and perfusate, as well as levels of soluble ephB4 in BAL were increased in OV, while soluble ephrinB2 BAL levels were increased in retrograde perfusion. BAL levels of ephrinB2 and ephB4 were also determined in vivo, including mice ventilated for 7 hours with normal‐volume ventilation (NVV) or high‐volume ventilation (HVV) with increased levels of ephB4 in HVV BAL compared to NVV. Retrograde perfusion in IPL is limited as a routine method to investigate effects due to collapse for yet unclear reasons. If successful, retrograde perfusion has an influence on pulmonary oedema formation. In BAL, ephrinB2 seems to be up‐regulated by flow reversal, while ephB4 is a marker for acute lung injury.

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C188‐9 reduces TGF‐β1‐induced fibroblast activation and alleviates ISO‐induced cardiac fibrosis in mice

et al. 2021

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Cardiac fibrosis is the final event of heart failure and is associated with almost all forms of cardiovascular disease. Cardiac fibroblasts (CFs), a major cell type in the heart, are responsible for regulating normal myocardial function and maintaining extracellular matrix homeostasis in adverse myocardial remodeling. In this study, we found that C188‐9, a small‐molecule inhibitor of signal transducer and activator of transcription 3 (STAT3), exhibited an antifibrotic function, both in vitro and in vivo. C188‐9 decreased transforming growth factor‐β1‐induced CF activation and fibrotic gene expression. Moreover, C188‐9 treatment alleviated heart injury and cardiac fibrosis in an isoproterenol‐induced mouse model by suppressing STAT3 phosphorylation and activation. These findings may help us better understand the role of C188‐9 in cardiac fibrosis and facilitate the development of new treatments for cardiac fibrosis and other cardiovascular diseases.

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EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling

Abstract: 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.

Cited by 118 publications

References 27 publications

Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination

Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination

Retrograde perfusion in isolated perfused mouse lungs—Feasibility and effects on cytokine levels and pulmonary oedema formation

C188‐9 reduces TGF‐β1‐induced fibroblast activation and alleviates ISO‐induced cardiac fibrosis in mice

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