Abstract 125: The E2F1 Transcription Factor Suppresses Cardiac Fibrosis via Downregulating Syndecan-4 Expression and Smad2/3 Phosphorylation
Rationale: The E2F1 transcription factor is best known as a cell-cycle regulator; recent reports suggest its important role in cardiovascular system.
Objective: To determine whether E2F1 regulates cardiac fibrosis.
Methods and Results: Following Angiotensin II (Ang II) administration, E2F1-null (E2F1-KO) mice displayed a more severe cardiac fibrosis and higher levels of cardiac phospho-Smad2 (pSmad2) and pSmad3 than WT mice. Consistently, levels of pSmad2 and pSmad3 were elevated in E2F1-KO fibroblasts, which was associated with a significantly increased expression of collagen I (Col I) and α-smooth muscle actin (α-SMA) and interestingly, cell surface proteoglycan syndecan-4 (Sdc4). Knockdown of Sdc4 significantly attenuated the elevation in Smad2/3 phosphorylation and Col I and α-SMA expression in E2F1-KO fibroblasts. Remarkably, either chemical inhibition of Smad2/3 signaling or morpholino-mediated knockdown of Sdc4 expression abrogated the difference in the degree of Ang II-induced cardiac fibrosis between WT and E2F1-KO animals.
Conclusions: E2F1 suppresses Ang II-induced cardiac fibrosis by downregulating Sdc4 expression and Sdc4-mediated Smad 2/3 activation.
Author Disclosures: D. Biyashev: None. C. Boriboun: None. A.K. Ghosh: None. S. Han: None. R. Kishore: None. D.W. Losordo: None. G. Qin: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2015 by American Heart Association, Inc.