Abstract 73: A Novel Role of E2F1 in Stress-induced Cardiac Fibrosis
Rationale: E2F1 transcription factor is best known as a cell cycle regulator. Recent reports indicate the importance of E2F1 in cardiovascular system, though its exact role is not clear. TGF-beta/Smad2,3 signaling pathway, on the other hand, has been long implicated in the regulation of cardiovascular health and numerous disease, including cardiac fibrosis. Interaction between these two major pathways has been reported in the cancer settings.
Objective: To identify the possible interactions between E2F1 and TGF-beta/Smad2,3 signaling pathways in cardiovascular system and determine the functional outcome of these interactions in cardiac health.
Methods and Results: E2F1-/- mice developed significantly higher degree of cardiac fibrosis than wild type mice in the Angiotensin II - induced cardiac fibrosis model. The levels of phosphorylated Smad2 and Smad3 were significantly higher in the hearts of E2F1-/- mice, as well as in mouse embryonic fibroblasts derived from E2F1-/- animals. Associated expression of collagen I was significantly increased in mouse embryonic fibroblasts derived from E2F1-/- animals, and treatment with TGF-beta resulted in higher collagen deposition compared to wild type fibroblasts. Treating animals with SB 431542, chemical inhibitor of Smad2,3 signaling, obliterated the difference in the degree of cardiac fibrosis between wild type and E2F1 knockout animals in the Ang II model. We discovered that levels of syndecan-4, heparan sulfate proteoglycan transmembrane protein implicated in fibrosis and known to interact with TGF-beta are significantly increased in both E2F1-/- fibroblasts and hearts. siRNA-mediated knockdown of syndecan-4 using siRNA resulted in decreased Smad2,3 phosphorylation in E2F1-/- MEFs. Similarly, down regulation of syndecan-4 in-vivo using morpholino lead to decreased cardiac fibrosis in E2F1-/- mice in Ang II model.
Conclusions: E2F1 suppresses activation of TGF-beta/Smad 2,3 pathway. The E2F1-dependent suppression of cardiac fibrosis through TGF-beta/Smad 2,3 pathway is at least partially regulated by syndecan-4.
Author Disclosures: D. Biyashev: None C. Boriboun: None G. Qin: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.