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

Yong Zhang; Xianxian Wu; Yang Li; Haiying Zhang; Zhange Li; Ying Zhang; Longyin Zhang; Jiaming Ju; Xin Liu; Xiaohui Chen; Peter V Glybochko; Vladimir Nikolenko; Philipp Kopylov; Chaoqian Xu; Baofeng Yang

doi:10.1038/srep33787

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

Sci Rep. 2016 Sep 27:6:33787. doi: 10.1038/srep33787.

Authors

Yong Zhang^{1

2}, Xianxian Wu¹, Yang Li³, Haiying Zhang¹, Zhange Li¹, Ying Zhang¹, Longyin Zhang¹, Jiaming Ju¹, Xin Liu¹, Xiaohui Chen¹, Peter V Glybochko⁴, Vladimir Nikolenko⁴, Philipp Kopylov⁵, Chaoqian Xu¹, Baofeng Yang^{1

6}

Affiliations

¹ Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
² Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150086, China.
³ Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province &Ministry of Health (23618504), Harbin Medical University, Harbin, 150081, China.
⁴ The Research Center, Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
⁵ Department of preventive and emergency cardiology, Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
⁶ Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, 3010, Australia.

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 (α-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-3β/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.