title: Snail as a potential target molecule in cardiac fibrosis: paracrine action of endothelial cells on fibroblasts through snail and CTGF axis.
abstract: Ischemia/reperfusion (I/R) injury to myocardium induces death of cardiomyocytes and destroys the vasculature, leading to cardiac fibrosis that is mainly mediated by the transdifferentiation of fibroblasts to myofibroblasts and the collagen deposition. Snail involvement in fibrosis is well known; however, the contribution of Snail to cardiac fibrosis during I/R injury and its underlying mechanisms have not been defined. We showed that I/R injury to mouse hearts significantly increases the expression of Snail. An in vitro hypoxia/reoxygenation (Hy/Reoxy) experiment showed that the cell source of Snail induction is endothelial cells rather than cardiac fibroblasts (cFibroblasts) or cardiomyoblasts. When Snail was overexpressed in endothelial cells, they underwent endothelial-to-mesenchymal transition (EndMT) but showed very poor capacity for collagen synthesis. Instead, reoxygenation- or Snail overexpression-mediated EndMT-like cells noticeably stimulated transdifferentiation of fibroblasts to myofibroblasts via secretion of connective tissue growth factor (CTGF). The injection of a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, a selective Snail inhibitor, remarkably suppressed collagen deposition and cardiac fibrosis in mouse I/R injury, and significantly improved cardiac function and reduced Snail and CTGF expression in vivo. Our findings suggested a new mechanism of cell-to-cell communication between EndMT-like cells and fibroblasts for fibrosis induction and implicated Snail as a potential target molecule in cardiac fibrosis after I/R injury.
authors.affiliation: Department of Internal Medicine and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Joo-Yun
authors.initials: JY
authors.lastname: Won
authors.forename: Woo Jean
authors.initials: WJ
authors.lastname: Kim
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Lee
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D058628:Myofibroblasts / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists; D051381:Rats; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D047495:PPAR gamma; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D055513:Connective Tissue Growth Factor