Abstract 19071: A Novel Role of E2f1 in the Regulation of Bone Marrow Progenitor Cell Oxidative Metabolism and Ischemic Cardiac Repair
Background: We have previously shown that knockout of E2F1 in mice enhances angiogenesis following induction of hind limb ischemia. Recent studies suggest that E2F1 can act as a switch between glycolysis and oxidative phosphorylation, and suppression of E2F1 enhances oxidative phosphorylation in a variety of cell types. Since an increase in oxidative phosphorylation in stem/progenitor cells is often associated with cell differentiation, we hypothesize that E2F1 regulates bone marrow (BM) progenitor cell differentiation thereby impacts on ischemic cardiac repair by switching metabolism status of the cells from glycolysis to oxidative phosphorylation.
Methods and Results: We cultured bone marrow (BM) Lin- progenitor cells under hypoxic and normxic conditions for 24 h, then measured the expression of metabolism related genesand evaluated cell proliferation and differentiation. We also performed adoptive BM transplantation to reconstitute BM of WT mice with E2F1-/- or WT BM, followed by surgical induction of myocardial infarction (MI), to compare the role of BM E2F1 in the cardiac repair in vivo. We found that the expression level of genes in the mitochondria respiration chain in the E2F1-/- BM Lin- progenitor cells is in average about 2 holds higher than those in WT cells (P<0.05, n=3). After culture in the EPC differentiation medium for 7 days, the expression levels of EPC markers, CD31 and KDR , were significantly higher in E2F1-/- cells than in WT control cells (P<0.05, n=3). Although there was no significant difference in the proliferating rate between WT and E2F1-/- BM Lin- progenitor cells cultured in normoxia, when cultured under hypoxic condition the proliferating rate of E2F1-/- cells were markedly greater than that of WT cells (P<0.05, n=3). Consistently, the infarcted size in mice transplanted with E2F1-/-eGFPTg BM was significantly smaller than in mice transplanted with WTeGFPTg BM (P<0.01, n=5).
Conclusions: Genetic deletion of E2F1 in the BM progenitor cells enhances oxidative metabolism that may result in enhanced differentiation towards endothelial lineage and increased proliferation in the ischemic/hypoxic tissue environment. Therefore, inhibition of E2F1 in BM progenitor cells may improve the recovery from cardiac ischemic injury.
- © 2013 by American Heart Association, Inc.