Abstract
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
• ERG is abundant in murine hearts, especially in cardiac ECs, but decreased during fibrotic remodeling.
• ERG knockdown causes spontaneously cardiac fibrosis and dysfunction.
• ERG silence in HUVECs promotes the secretion of endothelin-1, which in turn activates cardiac fibroblasts in a paracrine manner.
• Endothelial ERG overexpression prevents pressure overload-induced cardiac fibrosis.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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This work was supported by grants from National Natural Science Foundation of China (No: 81470516 and 81700254), the Key Project of the National Natural Science Foundation (No. 81530012), National Key R&D Program of China (2018YFC1311300), the Fundamental Research Funds for the Central Universities (No. 2042017kf0085 and 2042018kf1032), Development Center for Medical Science and Technology National Health and Family Planning Commission of the People’s Republic of China (The prevention and control project of cardiovascular disease, 2016ZX-008-01) and Science and Technology Planning Projects of Wuhan (2018061005132295).
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XZ, CH, and QZT contributed to the conception and design of the experiment. XZ, CH, YPY, PS, and CYK performed the study and participated in data acquisition. XZ, CH, HMW, SCX, and ZGM contributed to the data analysis and interpretation. ZX, ZGM, and QZT wrote and revised the manuscript. ZGM and QZT are the guarantors of this work. All authors approved the final version of the manuscript. CH and XZ contributed equally to this manuscript.
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Zhang, X., Hu, C., Yuan, YP. et al. Endothelial ERG alleviates cardiac fibrosis via blocking endothelin-1-dependent paracrine mechanism. Cell Biol Toxicol 37, 873–890 (2021). https://doi.org/10.1007/s10565-021-09581-5
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DOI: https://doi.org/10.1007/s10565-021-09581-5