Dataset Information

Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis.

ABSTRACT: Emerging evidence has suggested the critical role of endothelial to mesenchymal transition (EndMT) in fibrotic diseases. The present study was designed to examine whether EndMT is involved in arsenic trioxide (As₂O₃)-induced cardiac fibrosis and to explore the underlying mechanisms. Cardiac dysfunction was observed in rats after exposure to As₂O₃ for 15?days using echocardiography, and the deposition of collagen was detected by Masson's trichrome staining and electron microscope. EndMT was indicated by the loss of endothelial cell markers (VE-cadherin and CD31) and the acquisition of mesenchymal cell markers (?-SMA and FSP1) determined by RT-PCR at the mRNA level and Western blot and immunofluorescence analysis at the protein level. In the in-vitro experiments, endothelial cells acquired a spindle-shaped morphology accompanying downregulation of the endothelial cell markers and upregulation of the mesenchymal cell markers when exposed to As₂O₃. As₂O₃ activated the AKT/GSK-3?/Snail signaling pathway, and blocking this pathway with PI3K inhibitor (LY294002) abolished EndMT in As₂O₃-treated endothelial cells. Our results highlight that As₂O₃ is an EndMT-promoting factor during cardiac fibrosis, suggesting that targeting EndMT is beneficial for preventing As₂O₃-induced cardiac toxicity.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5037371 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis.

Zhang Yong Y Wu Xianxian X Li Yang Y Zhang Haiying H Li Zhange Z Zhang Ying Y Zhang Longyin L Ju Jiaming J Liu Xin X Chen Xiaohui X Glybochko Peter V PV Nikolenko Vladimir V Kopylov Philipp P Kopylov Philipp P Xu Chaoqian C Yang Baofeng B

Scientific reports 20160927

Emerging evidence has suggested the critical role of endothelial to mesenchymal transition (EndMT) in fibrotic diseases. The present study was designed to examine whether EndMT is involved in arsenic trioxide (As2O3)-induced cardiac fibrosis and to explore the underlying mechanisms. Cardiac dysfunction was observed in rats after exposure to As2O3 for 15 days using echocardiography, and the deposition of collagen was detected by Masson's trichrome stain ...[more]

PMID: 27671604

Similar Datasets

Project description:Rationale: Cardiac fibrosis is an integral constituent of every form of chronic heart disease, and persistence of fibrosis reduces tissue compliance and accelerates the progression to heart failure. Relaxin-2 is a human hormone, which has various physiological functions such as mediating renal vasodilation in pregnancy. Its recombinant form Serelaxin has recently been tested in clinical trials as a therapy for acute heart failure but did not meet its primary endpoints. The aim of this study is to examine whether Serelaxin has an anti-fibrotic effect in the heart and therefore could be beneficial in chronic heart failure. Methods: We utilized two different cardiac fibrosis mouse models (ascending aortic constriction (AAC) and Angiotensin II (ATII) administration via osmotic minipumps) to assess the anti-fibrotic potential of Serelaxin. Histological analysis, immunofluorescence staining and molecular analysis were performed to assess the fibrosis level and indicate endothelial cells which are undergoing EndMT. In vitro TGFβ1-induced endothelial-to-mesenchymal transition (EndMT) assays were performed in human coronary artery endothelial cells and mouse cardiac endothelial cells (MCECs) and were examined using molecular methods. Chromatin immunoprecipitation-qPCR assay was utilized to identify the Serelaxin effect on chromatin remodeling in the Rxfp1 promoter region in MCECs. Results: Our results demonstrate a significant and dose-dependent anti-fibrotic effect of Serelaxin in the heart in both models. We further show that Serelaxin mediates this effect, at least in part, through inhibition of EndMT through the endothelial Relaxin family peptide receptor 1 (RXFP1). We further demonstrate that Serelaxin administration is able to increase its own receptor expression (RXFP1) through epigenetic regulation in form of histone modifications by attenuating TGFβ-pSMAD2/3 signaling in endothelial cells. Conclusions: This study is the first to identify that Serelaxin increases the expression of its own receptor RXFP1 and that this mediates the inhibition of EndMT and cardiac fibrosis, suggesting that Serelaxin may have a beneficial effect as anti-fibrotic therapy in chronic heart failure.

Project description:The dose-dependent toxicity to cardiomyocytes has been well recognized as a central characteristic of doxorubicin (DOX)-induced cardiotoxicity (DIC), however, the pathogenesis of DIC in the cardiac microenvironment remains elusive. Irisin is a new hormone-like myokine released into the circulation in response to exercise with distinct functions in regulating apoptosis, inflammation, and oxidative stress. Recent advances revealed the role of irisin as a novel therapeutic method and an important mediator of the beneficial effects of exercise in cardioprotection. Here, by using a low-dose long-term mouse DIC model, we found that the perivascular fibrosis was involved in its myocardial toxicity with the underlying mechanism of endothelial-to-mesenchymal transition (EndMT). Irisin treatment could partially reverse DOX-induced perivascular fibrosis and cardiotoxicity compared to endurance exercise. Mechanistically, DOX stimulation led to excessive accumulation of ROS, which activated the NF-κB-Snail pathway and resulted in EndMT. Besides, dysregulation of autophagy was also found in DOX-treated endothelial cells. Restoring autophagy flux could ameliorate EndMT and eliminate ROS. Irisin treatment significantly alleviated ROS accumulation, autophagy disorder, NF-κB-Snail pathway activation as well as the phenotype of EndMT by targeting uncoupling protein 2 (UCP2). Our results also initially found that irisin was mainly secreted by cardiomyocytes in the cardiac microenvironment, which was significantly reduced by DOX intervention, and had a protective effect on endothelial cells in a paracrine manner. In summary, our study indicated that DOX-induced ROS accumulation and autophagy disorders caused an EndMT in CMECs, which played a role in the perivascular fibrosis of DIC. Irisin treatment could partially reverse this phenomenon by regulating UCP2. Cardiomyocytes were the main source of irisin in the cardiac microenvironment. The current study provides a novel perspective elucidating the pathogenesis and the potential treatment of DIC.

Project description:Intraflagellar transport protein 88 (Ift88) is required for ciliogenesis and shear stress-induced dissolution of cilia in embryonic endothelial cells coincides with endothelial-to-mesenchymal transition (EndMT) in the developing heart. EndMT is also suggested to underlie heart and lung fibrosis, however, the mechanism linking endothelial Ift88, its effect on EndMT and organ fibrosis remains mainly unexplored. We silenced Ift88 in endothelial cells (ECs) in vitro and generated endothelial cell-specific Ift88-knockout mice (Ift88endo) in vivo to evaluate EndMT and its contribution towards organ fibrosis, respectively. Ift88-silencing in ECs led to mesenchymal cells-like changes in endothelial cells. The expression level of the endothelial markers (CD31, Tie-2 and VE-cadherin) were significantly reduced with a concomitant increase in the expression level of mesenchymal markers (αSMA, N-Cadherin and FSP-1) in Ift88-silenced ECs. Increased EndMT was associated with increased expression of profibrotic Collagen I expression and increased proliferation in Ift88-silenced ECs. Loss of Ift88 in ECs was further associated with increased expression of Sonic Hedgehog signaling effectors. In vivo, endothelial cells isolated from the heart and lung of Ift88endo mice demonstrated loss of Ift88 expression in the endothelium. The Ift88endo mice were born in expected Mendelian ratios without any adverse cardiac phenotypes at baseline. Cardiac and pulmonary endothelial cells isolated from the Ift88endo mice demonstrated signs of EndMT and bleomycin treatment exacerbated pulmonary fibrosis in Ift88endo mice. Pressure overload stress in the form of aortic banding did not reveal a significant difference in cardiac fibrosis between Ift88endo mice and control mice. Our findings demonstrate a novel association between endothelial cilia with EndMT and cell proliferation and also show that loss of endothelial cilia-associated increase in EndMT contributes specifically towards pulmonary fibrosis.

Dataset Information

Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis.

Publications

Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets