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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

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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

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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.

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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.

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