CARDIAC OUTFLOW TRACT REMODELING BY MYOCYTE APOPTOSIS

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (adapted from the applicant's description): The transition of the embryonic heart from a single to a dual circulation requires remodeling of the cardiac outflow tract (OFT). This remodeling involves shortening and rotation of the myocardial portion of the OFT, and division of the single lumen by septation. These processes result in a heart in which the pulmonary artery (PA) connects to the right ventricle (RV) and to the right of the aorta that connects directly to the left ventricle. In a number of congenital human heart defects, i.e., conotruncal defects, there is a misalignment of the myocardial infundibulum with the great vessels. The lab has shown using a recombinant adenovirus (CMV promoter) that shortening of the OFT occurred between ED5-8 during chick development with the OFT myocardium comprising the infundibular connection of the RV to the PA. Concomitant with OFT shortening was a high incidence of apoptosis of the OFT cardiomyocytes, and activation of the caspase cascade. The hypothesis is that OFT myocyte apoptosis is necessary for OFT shortening and rotation, and that perturbations of OFT myocyte apoptosis will result in defects in the ventriculo-arterial connections modeling human conotruncal defects. Aims include 1) targeting inhibitors of apoptosis to the OFT myocardium with the adenovirus; 2) precociously activating apoptosis in the OFT myocardium via the fas receptor; and 3) examining the molecular pathway responsible for the tightly regulated apoptosis of the OFT cardiomyocytes, specifically the BMP-mediated pathway.