Abstract 1249: Atrial Septal Defects Caused By Endocardial Specific Deficiency Of Transcription Factor Tbx5
In human, mutations in transcription factor Tbx5 cause the Holt Oram syndrome (HOS) characterized by forelimb and a large spectrum of cardiac malformations ranging from simple arrhythmia to complex structural defects. Valvular and atrial septal defects (ASDs) are the most common cardiac malformations found in patients with HOS. Since these structures are largely of endocardial origin, we tested the contribution of endocardial Tbx5 to heart morphogenesis and to cardiac malformations found in HOS. Endocardium specific deletion of Tbx5 was accomplished by breeding Tbx5 flox mice with tie2-cre transgenic mice. Genotyping of resulting offsprings showed the expected genotypes in a Mendelian ratio indicating that removal of Tbx5 from endocardial cells is not embryonic lethal. However, mice lacking Tbx5 in the endocardium had a secundum type atrial septal defect (ASD) in the knock out mice and a patent foramen oval (PFO) in the heterozygote mice. A dysregulation of the mitral valve blood flow was also evident in the eTbx5−/− mice consistent with pulmonary hypertension caused by the ASD. The impact of the cardiac defect on exercise tolerance was assessed using tread mill evaluation. The results reveal an exquisite eTbx5 dose-dependence for exercise tolerance. Apoptag assay demonstrated excessive apoptosis of the septum primum in eTbx5−/− mice suggesting that Tbx5 may be involved in endocardial cell survival. Transient transfections with GATA-4 and Tbx5 on the Bcl-X promoter indicated that Tbx5 activates Bcl-X promoter and enhances GATA-4 transcriptional activation. Moreover, overexpression of Tbx5 in endocardial cell progenitors induced endogenous Bcl-X expression. Together, the results indicate that Tbx5 is an essential regulator of endocardial cells and that defective endocardial Tbx5 results in congenital heart disease.