RESUMO
RATIONALE: The development of the cardiac outflow tract (OFT) and great vessels is a complex process that involves coordinated regulation of multiple progenitor cell populations. Among these populations, neural crest cells make important contributions to OFT formation and aortic arch remodeling. Although numerous signaling pathways, including Notch, have been implicated in this process, the role of epigenetics in OFT development remains largely unexplored. OBJECTIVE: Because histone deacetylases (Hdacs) play important roles in the epigenetic regulation of mammalian development, we have investigated the function of Hdac3, a class I Hdac, during cardiac neural crest development in mouse. METHODS AND RESULTS: Using 2 neural crest drivers, Wnt1-Cre and Pax3(Cre), we show that loss of Hdac3 in neural crest results in perinatal lethality and cardiovascular abnormalities, including interrupted aortic arch type B, aortic arch hypoplasia, double-outlet right ventricle, and ventricular septal defect. Affected embryos are deficient in aortic arch artery smooth muscle during midgestation, despite intact neural crest cell migration and preserved development of other cardiac and truncal neural crest derivatives. The Hdac3-dependent block in smooth muscle differentiation is cell autonomous and is associated with downregulation of the Notch ligand Jagged1, a key driver of smooth muscle differentiation in the aortic arch arteries. CONCLUSIONS: These results indicate that Hdac3 plays a critical and specific regulatory role in the neural crest-derived smooth muscle lineage and in formation of the OFT.
Assuntos
Coração Fetal/enzimologia , Cardiopatias Congênitas/enzimologia , Histona Desacetilases/fisiologia , Músculo Liso/patologia , Crista Neural/patologia , Timo/anormalidades , Medula Suprarrenal/embriologia , Animais , Aorta Torácica/anormalidades , Diferenciação Celular/fisiologia , Linhagem da Célula , Movimento Celular , Dupla Via de Saída do Ventrículo Direito/embriologia , Dupla Via de Saída do Ventrículo Direito/enzimologia , Dupla Via de Saída do Ventrículo Direito/genética , Feminino , Coração Fetal/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Comunicação Interventricular/embriologia , Comunicação Interventricular/enzimologia , Comunicação Interventricular/genética , Ventrículos do Coração/embriologia , Ventrículos do Coração/enzimologia , Histona Desacetilases/deficiência , Histona Desacetilases/genética , Masculino , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/fisiologia , Receptores Notch/fisiologia , Proteína Wnt1/fisiologiaRESUMO
Plasma renin activity was estimated in 11 infants with severe congestive heart failure. The infants had congenital heart disease with left to right shunts and were receiving diuretic treatment. Plasma renin activity was measured by radioimmunoassay of generated concentrations of angiotensin I. The mean (SD) plasma renin activity was 84 (21) ng angiotensin I/ml/hour, which is considerably above normal infant values. A hyperactive renin-angiotensin system may be detrimental in these patients. Angiotensin converting enzyme inhibitors may be of value in treating infants with severe congestive heart failure.
