Snail as a potential target molecule in cardiac fibrosis: Paracrine action of endothelial cells on fibroblasts through snail and CTGF Axis

Sae Won Lee, Joo Yun Won, Woo Jean Kim, Jaewon Lee, Kyung Hee Kim, Seock Won Youn, Ju Young Kim, Eun Ju Lee, Yong Jin Kim, Kyu Won Kim, Hyo Soo Kim

Research output: Contribution to journalArticle

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1767-1777
Number of pages11
JournalMolecular Therapy
Volume21
Issue number9
DOIs
StatePublished - Sep 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Snail as a potential target molecule in cardiac fibrosis: Paracrine action of endothelial cells on fibroblasts through snail and CTGF Axis'. Together they form a unique fingerprint.

  • Cite this

    Lee, S. W., Won, J. Y., Kim, W. J., Lee, J., Kim, K. H., Youn, S. W., Kim, J. Y., Lee, E. J., Kim, Y. J., Kim, K. W., & Kim, H. S. (2013). Snail as a potential target molecule in cardiac fibrosis: Paracrine action of endothelial cells on fibroblasts through snail and CTGF Axis. Molecular Therapy, 21(9), 1767-1777. https://doi.org/10.1038/mt.2013.146