Abstract 175: Genetic Ablation Of S-nitrosoglutathione Reductase In Mice Enhances Proliferative Expansion Of Adult Heart Progenitors And Myocytes Post Myocardial Infarction
Objectives: The molecular pathways underlying the proliferative activity of adult cardiac myocytes and stem/progenitors in response to heart damage remain elusive. Since perturbing nitroso-redox balance in mice by genetic deletion of GSNOR (GSNOR-/-) confers resilience to experimental myocardial infarction (MI), we investigated whether GSNOR knockout influences the proliferative activity of the post-MI heart.
Hypothesis: Knockout of GSNOR in mice enhances the proliferative expansion of CMs and cKit+ cardiac stem cells (CSCs) in response to MI.
Methods: Wild-type (WT) and GSNOR-/- mice (n=5/ group) underwent experimental MI. To assess proliferative activity, animals received intraperitoneal injections of 5-bromodeoxyuridine (BrdU) at selected time-points during the first 2 weeks post-MI. Immunnohistochemical evaluation was performed 1 month post-MI.
Results: Confocal immunofluorescence revealed that GSNOR-/- hearts exhibited higher rates of BrdU incorporation in CSCs after MI (10.9%±4.99% of WT CSCs compared to 15.9%±3% of GSNOR-/- CSCs, p=0.02). Similarly, there were ~3-fold more BrdU+/Tropomyosin+ cardiomyocytes in the infarct zone of GSNOR-/- mice compared to WT (p<0.05). Immunohistochemical evaluation of cardiac troponin-T+ cardiomyocytes co-expressing the mitotic marker ser-10 phosphorylated histone H3 (H3P) showed further that cardiomyocyte mitosis was 2.4-fold greater in GSNOR-/- compared to WT mice (p<0.05), whereas the presence of aurora-b kinase in the cleavage furrow of GSNOR-/- cardiomyocytes substantiated their competence for mitosis after MI. The rate of cardiomyocyte apoptosis after MI, was not different between GSNOR-/- and WT mice, as shown by activated cleaved caspase-3 immunofluorescence.
Conclusions: Collectively, our findings suggest that protein S-nitrosothiol turnover by GSNOR regulates proliferation of cardiomyocytes and CSCs in the adult heart in response to damage. These findings have therapeutic implications for the treatment of heart disease since they reveal novel pathways by which nitroso-redox balance influences cardiac repair.
Author Disclosures: K.E. Hatzistergos: 7. Ownership Interest; Significant; Vestion Inc.. 8. Consultant/Advisory Board; Significant; Vestion Inc. E.C. Paulino: None R.A. Dulce: None L.M. Takeuchi: None S. Kulandavelu: None W. Balkan: None R.M. Kanashiro-Takeuchi: None. J.M. Hare: 7. Ownership Interest; Significant; Vestion Inc, Heart Genomics. 8. Consultant/Advisory Board; Significant; Vestion Inc, Heart Genomics.
- © 2014 by American Heart Association, Inc.