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.
Highlights
The transformation of vascular endothelial cells into myofibroblasts is a process known as endothelial-to-mesenchymal transition (EndMT), which was first identified in the embryonic development of the heart[14]
We explored the potential role of As2O3 in triggering EndMT to form cardiac fibrosis, and investigated the signaling pathway leading to EndMT in human aortic endothelial cells (HAECs)
We made an effort to understand the potential role of EndMT in As2O3-induced cardiac fibrosis
Summary
The transformation of vascular endothelial cells into myofibroblasts is a process known as endothelial-to-mesenchymal transition (EndMT), which was first identified in the embryonic development of the heart[14]. As a special form of epithelial to mesenchymal transition (EMT), EndMT is involved in the development of cardiac fibrosis and other fibrotic diseases[15,16,17,18,19]. During the process of EndMT, endothelial cells lose their original phenotypes and eventually transform into a mesenchymal or myofibroblastic phenotypes with adoption of the migratory properties and acquisition of mesenchymal cell markers such as α-SMA and fibrotic-specific protein 1(FSP1)[17]. We explored the potential role of As2O3 in triggering EndMT to form cardiac fibrosis, and investigated the signaling pathway leading to EndMT in human aortic endothelial cells (HAECs)
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