Abstract 305: E2F1 Suppresses Cardiac Fibrosis
E2F1 transcription factor is best known for regulation of cell cycle; its role in the cardiovascular system is not well understood. In a transcriptome analysis, we detected a significantly elevated level in the expression of collagen I and alpha-smooth muscle actin in the E2F1-null (E2F1-/-) mouse embryonic fibroblasts (MEFs) as compared to wild-type (WT) MEFs. Levels of Smad 2 and Smad 3 were also significantly higher in E2F1-/- MEFs. In addition, treatment with TGF-beta (10 ng/ml) induced a greater degree of Smad 2 and Smad 3 phosphorylation in E2F1-/- MEFs than in WT MEFs. Interestingly, these in vitro observations were corroborated with our results obtained from mouse heart samples: the basal levels of both total and phosphorylated Smad 2 were significantly higher in the E2F1-/- heart than in the WT heart (n=3). To understand the significance of these findings in the pathogenesis of cardiac fibrosis, we administered Angiotensin II (3 mg/kg/day) to animals for 7 or 14 days with a subcutaneous osmotic minipump. The total area of cardiac fibrosis was significantly greater in the E2F1-/- mice than in WT littermates (E2F1-/- vs. WT: 17+/-3.8% vs. 6+/-2.6%, p<0.05). Thus, we disclose a novel role of E2F1 in the control of Smad signaling that may limit the development of fibrosis in the stressed heart.
- © 2013 by American Heart Association, Inc.