Abstract 583: Cardiac Compensation In ErbB2-deficient Zebrafish Embryos

Abstract

Congenital heart diseases are a leading birth defect in infants and often feature structural malformations that arise during embryogenesis. Over the course of development, the cardiac chambers undergo extensive morphogenetic changes to optimize their myoarchitecture for efficient conduction and contraction, most notably is the formation of luminal, muscular protrusions called trabeculae within the ventricle. Altered trabeculation is associated with congenital heart diseases, and failure to form trabeculae is embryonic lethal. We have previously reported that ErbB2 signaling plays a direct and essential role in cardiac trabeculation, and erbb2 mutant hearts develop progressive cardiac dysfunction with reduced fractional shortening, and eventually fail. However, the mechanism underlying this functional deterioration in the absence of trabecular formation is not known. In this study, we found that the trabeculae-deficient erbb2 mutant exhibited increased ventricular cardiomyocyte cross-sectional area and myofibril size, a phenotype reminiscent of that of an adult mammalian heart subjected to mechanical overload. Consistently, inhibition of Target of Rapamycin (TOR) signaling by rapamycin suppressed erbb2 mutant hypertrophic-like (HL) growth phenotype. Additional studies suggest the erbb2 mutant HL phenotypes are due to a loss of cardiac trabeculae. We thus propose that trabeculae serve to enhance contractility and that defects in this process lead to wall-stress induced pathological hypertrophic remodeling.