PMID- 26656263 OWN - NLM STAT- MEDLINE DCOM- 20160429 LR - 20171116 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 144 DP - 2016 Jan 1 TI - Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway. PG - 208-17 LID - S0024-3205(15)30088-6 [pii] LID - 10.1016/j.lfs.2015.11.025 [doi] AB - AIMS: Hydrogen sulfide (H2S) ameliorates cardiac fibrosis in several models by suppressing endoplasmic reticulum (ER) stress. Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of cardiac fibrosis. Therefore, we investigated whether H2S could attenuate EndMT by suppressing ER stress. MAIN METHODS: ER stress was induced by tunicamycin (TM) and thapsigargin (TG) and inhibited by 4-phenylbutyrate (4-PBA) in human umbilical vein endothelial cells (HUVECs). ER stress and EndMT were measured by Western blot, Real-Time PCR and immunofluorescence staining. Inhibition Smad2 and Src pathway were performed by specific inhibitors and siRNA. Ultrastructural examination was detected by transmission electron microscope. The functions of HUVECs were investigated by cell migration assay and tube formation in vitro. KEY FINDINGS: Under ER stress, the expression of endothelial marker CD31 significantly decreased while mesenchymal markers alpha-SMA, vimentin and collagen 1 increased which could be inhibited by 4-PBA. Moreover, HUVECs changed into a fibroblast-like appearance with the activation of Smad2 and Src kinase pathway. After inhibiting Src pathway, EndMT would be significantly inhibited. TM reduced H2S levels in cell lysate and H2S pretreatment could preserve endothelial cell appearance with decreased ER stress and ameliorated dilation of ER. H2S could also downregulate the mesenchymal marker expression, and upregulate the endothelial markers expression, accompanied with the suppression of Src pathway. Moreover, H2S partially restored the capacity of migration and tube formation in HUVECs. SIGNIFICANCE: These results revealed that H2S could protect against ER stress-induced EndMT through Src pathway, which may be a novel role for the cardioprotection of H2S. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Ying, Ru AU - Ying R AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. FAU - Wang, Xiao-Qiao AU - Wang XQ AD - Department of Anesthesia, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, People's Republic of China. FAU - Yang, Ying AU - Yang Y AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. FAU - Gu, Zhen-Jie AU - Gu ZJ AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. FAU - Mai, Jing-Ting AU - Mai JT AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. FAU - Qiu, Qiong AU - Qiu Q AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. FAU - Chen, Yang-Xin AU - Chen YX AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. Electronic address: tjcyx1995@163.com. FAU - Wang, Jing-Feng AU - Wang JF AD - Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. Electronic address: dr_wjf@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151202 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - 0 (Platelet Endothelial Cell Adhesion Molecule-1) RN - 0 (RNA, Small Interfering) RN - 0 (SMAD2 protein, human) RN - 0 (Smad2 Protein) RN - EC 2.7.10.2 (src-Family Kinases) RN - YY9FVM7NSN (Hydrogen Sulfide) SB - IM MH - Down-Regulation/drug effects MH - Endoplasmic Reticulum Stress/*drug effects MH - Epithelial-Mesenchymal Transition/*drug effects MH - Fibrosis MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Hydrogen Sulfide/*pharmacology MH - Platelet Endothelial Cell Adhesion Molecule-1/metabolism MH - RNA, Small Interfering/pharmacology MH - Signal Transduction/drug effects MH - Smad2 Protein/antagonists & inhibitors/physiology MH - Unfolded Protein Response/drug effects MH - src-Family Kinases/*drug effects/*physiology OTO - NOTNLM OT - Endoplasmic reticulum stress OT - Endothelial-to-mesenchymal transition OT - Epithelial-to-mesenchymal transition OT - Human umbilical vein endothelial cells OT - Hydrogen sulfide OT - Unfolded protein response EDAT- 2015/12/15 06:00 MHDA- 2016/04/30 06:00 CRDT- 2015/12/15 06:00 PHST- 2015/06/21 00:00 [received] PHST- 2015/10/20 00:00 [revised] PHST- 2015/11/24 00:00 [accepted] PHST- 2015/12/15 06:00 [entrez] PHST- 2015/12/15 06:00 [pubmed] PHST- 2016/04/30 06:00 [medline] AID - S0024-3205(15)30088-6 [pii] AID - 10.1016/j.lfs.2015.11.025 [doi] PST - ppublish SO - Life Sci. 2016 Jan 1;144:208-17. doi: 10.1016/j.lfs.2015.11.025. Epub 2015 Dec 2.