Abstract 15571: Pathological Stress Response in Adult Hearts after Disturbed Prenatal Development
The embryonic mouse heart has recently been shown to have a remarkable regenerative capacity in response to tissue mosaicism for mitochondrial dysfunction. Despite the functional loss of 50% of myocardial cells at midgestation the population of healthy cells can generate a functional heart by birth. However, we hypothesized that embryonic heart regeneration impacts on postnatal cardiac growth and function. We therefore analyzed mouse hearts after prenatal regeneration using echocardiography and histological as well as protein and gene expression data under baseline and Angiotensin II mediated stress conditions. Neonatal hearts after embryonic regeneration have a reduced heart weight/body weight ratio compared to controls and exhibit thin ventricular walls as well as myocardial non-compaction. Cardiomyocyte size is significantly increased which is accompanied by premature terminal differentiation of neonatal cardiomyocytes as revealed by an increased ratio of bi- versus mononucleated cells. Surprisingly, hearts after embryonic regeneration possess normal baseline LV function at any postnatal stage. However, in regenerated adult hearts cardiomyocyte hypertrophy is evident which is associated with activation of Akt and upregulation of IGF I. Angiotensin II mediated cardiac stress does not affect LV function or morphology in hearts that had undergone embryonic regeneration compared to controls. However, Ang II induces dramatic cardiomyocyte hypertrophy in regenerated hearts resulting in a doubling of cardiomyocyte size (98% increase compared to baseline versus 38% in controls). This overshooting hypertrophy is accompanied by increased expression of hypertrophy markers (BNP, ANP and Myh7), inhibition of p38 MAPK and activation of Stat3 signaling. Stat3 activation was confirmed by increased expression of target genes such as c-myc and Socs3 while expression of upstream activating cytokines (Il6, LIF, cardiotrophin) was unchanged. In conclusion, these data reveal that although hearts are functionally normal after embryonic heart regeneration they show a pathologic response to cardiac stress. This suggests that impaired myocardial development renders the heart more susceptible to cardiac stress and heart disease later in life.
- © 2010 by American Heart Association, Inc.