Abstract P004: Cardiac Regeneration in Neonatal Mice Following Ischemic Injury
As a consequence of the adult mammalian heart's limited regenerative capacity, ischemic heart disease is the leading cause of morbidity and mortality in the developed world. We have recently identified a brief window during post-natal development when the mammalian heart retains significant cardiac regenerative potential. Similar to adult zebrafish, the 1 day-old neonatal mouse heart is capable of complete cardiac regeneration following amputation of the entire ventricular apex. One major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia. Here, we demonstrate that the neonatal mouse heart is also capable of undergoing a cardiac regenerative response to replace lost cardiomyocytes following myocardial ischemia. Following permanent ligation of the left anterior descending (LAD) coronary artery of 1 day-old neonatal mice, we documented evidence of significant cardiac injury and myocyte death by histology and echocardiography at 1 and 4 days after LAD ligation (Ejection Fraction (MI vs. Sham) = 70.9±10.1% vs. 98.6±0.3%, P<0.05). Remarkably, the 1 day-old neonatal mouse heart completely regenerated the necrotic myocardium within 21 days, with minimal fibrosis and full recovery of cardiac function (Ejection Fraction (MI vs. Sham) = 94.6±1.4% vs. 97.9±0.1%). Similar to the regenerative response of neonatal mice to apical resection, the regenerative response of the neonatal mouse heart to ischemic injury was associated with robust and widespread activation of cardiomyocyte proliferation (∼11-fold), which peaked at day 7 post-injury. In contrast, following LAD ligation at 7 days-of-age, the cardiac regenerative response of neonatal mice was significantly impaired and by 14 days-of-age, the cardiac injury response was characterized by a fibrotic repair process that was reminiscent of the adult heart's response to ischemic injury. Additionally, over-expression of miR-195, a potent inhibitor of cardiomyocyte proliferation, impaired the cardiac regenerative response of neonatal mice. Thus, the neonatal mammalian heart is capable of complete regeneration following ischemic myocardial necrosis and cardiomyocyte proliferation appears to play an important role in this process.
- © 2011 by American Heart Association, Inc.