title: Fas ligand gene transfer to the embryonic heart induces programmed cell death and outflow tract defects.
abstract: The remodeling of the embryonic avian cardiac outflow tract (OFT) involves the removal of cardiomyocytes by programmed cell death (PCD). In contrast, the prevalence of PCD is low in the atrial or ventricular myocytes during this period of development. To determine if this selective PCD is due to the unique ability of the OFT cardiomyocytes to execute PCD, we transduced the embryonic chicken heart in ovo with recombinant adenovirus expressing a death (FasL) ligand. This resulted in programmed cell death in atrial, ventricular, and OFT cardiomyocytes as evidenced by chromosomal fragmentation, accumulation of lysosomes, and Caspase enzymatic activity. Consistent with the widespread induction of PCD, transcripts for the Fas receptor were detected in all chambers of the heart throughout development. The precocious and widespread activation of PCD in the OFT myocardium resulted in a marked dimunition of the subpulmonic myocardial infundibulum, and transposition of the aorta side-by-side with the pulmonary artery and connecting to the right ventricle. Defects in other cardiac structures are also described. We conclude that the regulated removal of OFT cardiomyocytes by PCD is required for the great vessels to make their proper connections with the ventricles in the transition to a dual circulation. The malalignment of the great vessels described in this animal model are similar to those described in congenital human conotruncal heart defects, suggesting that PCD-dependent remodeling of the OFT myocardium could be a target of genetic mutations or teratogens that cause human conotruncal heart defects.
authors.affiliation: Department of Pediatrics (Cardiology), Case Western Reserve School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Denver
authors.initials: D
authors.lastname: Sallee
authors.forename: Yaling
authors.initials: Y
authors.lastname: Qiu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Michiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Steven A
authors.initials: SA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002642:Chick Embryo; D017931:DNA Primers; D053222:Fas Ligand Protein; D015870:Gene Expression; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology*; D006652:Histological Techniques; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009024:Morphogenesis; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
chemical_list: D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D020169:Caspases