Abstract 16253: The DNA Glycosylase Neil3 Regulates Stem Cell Recruitment, Cell Proliferation and DNA Repair Following Myocardial Infarction
Background: Accumulation of DNA damage by impaired base excision repair (BER) could play a role in the pathogenesis of myocardial failure. The DNA glycosylase Neil3 is known to carry out BER during oxidative stress induced DNA damage. In addition we have previously demonstrated that Neil3 is localized to stem-cell rich areas in the neonatal murine brain and that Neil3-/- mice display only 50% DCX positive progenitor cells in the corpus striatum 3 days after induction of cerebral hypoxia/ischemia, as compared to wild type mice (WT). We therefore hypothesized that Neil3 plays an important role in myocardial remodeling and regeneration following myocardial infarction (MI), potentially involving BER mechanisms as well as stem cell physiology.
Methods and results: Myocardial gene expression of several DNA glycosylases were up-regulated in the murine post-MI heart failure (HF) model, with particularly enhanced expression of Neil3 (18-fold and 5.2-fold increase [3 days], 13-fold and 5.8-fold increase [7 days] and 2.6-fold and no increase [21 days] post-MI in infarcted and non-infarcted left ventricular (LV) tissue, respectively). Moreover, we found increased Neil3 expression (8.4-fold) in myocardial biopsies from HF patients, which significantly decreased following improvement of myocardial function during LV assist device treatment. Studying Neil3-/- mice, we found a significantly lower number of Sca-1 positive stem cells in the heart. Likewise, cardiospheres from adult Neil3-/- mice derived in vitro were significantly smaller than those from WT mice.
Conclusion: Our data suggest that the DNA glycosylase Neil3 has a role in regulating stem cells and cell differentiation and proliferation, in addition to its role in DNA repair, during development of post-MI HF.
- © 2011 by American Heart Association, Inc.