Abstract 527: E2F1 Regulates Syndecan-4 Expression Under Hypoxia
The E2F1 transcription factor is known to activate the genes involved in cell cycle progression. However, previous results published by our laboratory showed that the E2F1 plays a crucial role in the regulation of in vivo angiogenesis in mouse hind limb ischemia model. More recently, we demonstrated that E2F1-null (E2F1-/-) mice have a significantly better heart function than wild-type (WT) animals after surgically-induced myocardial infarction (MI). E2F1-/- mice display reduced endothelial cell (EC) apoptosis, increased EC proliferation, and enhanced angiogenesis in the infarcted heart.
To gain mechanistic insights into the role of E2F1 in modulating cellular response to ischemia/hypoxia, we analyzed global gene expression (Illumina microarray) in WT and E2F1-/- mouse embryonic fibroblasts after treatment with hypoxia (0.5% oxygen) or culture under normoxia for 8 h (n=4). The expression patterns of more than 25,000 genes were analyzed.
Among the validated genes syndecan-4, a member of transmembrane proteoglycan family was highly upregulated by hypoxia in E2F1-/- cells (p<0.01, n=4). Syndecan-4 is a transmembrane heparan sulfate proteoglycan involved in modulation of cell adhesion, migration, growth factor-mediated signaling, and angiogenesis. It is known to possess pro-angiogenic and anti-apoptotic properties, and in humans the levels of syndecan-4 are drastically increased in the border region of damaged cardiac tissue following MI. In mice, loss of syndecan-4 was shown to increase cardiac cell apoptosis, worsen myocardial remodeling, and provoke cardiac rupture after induced ischemic injury.
We confirmed our findings by measuring the levels of syndecan-4 expression in the hearts of WT and E2F1-/- animals after MI. Consistently, we found that the levels of syndecan-4 expression were significantly higher in the E2F1-/- mice than in WT mice (p<0.05, n=4).
Our results suggest that there exist a novel mechanism linking E2F1 and syndecan-4 to the regulation of cardiac ischemic angiogenesis.
- © 2012 by American Heart Association, Inc.