Study Of Akt Lsoforms In Heart Development

Mammals have three Akt/PKB (protein kinase B) isoforms, termed Akt1/PKBa, Akt2/PKBβ, and Akt3/PKBy (hereafter collectively referred to as Akt), that are encoded by three distinct genes localized on different chromosomes. Although the three Akt proteins share high homology and display similar domain structures, mouse genetic studies have demonstrated that they play overlapping but distinct roles in development and physiology. The P13K-PDK1-PKB/Akt (P13K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase) signaling pathway plays critical roles in a variety of biological processes, including cell survival, growth and proliferation, metabolism and organogenesis.Akt1-deficient mice have a high rate of neonatal mortality with an unknown cause. Here, we report that histological analysis revealed that Akt1-deficient embryos and newborns have heart defects and a decreased rate of cell proliferation. In addition, echocardiography demonstrated that the heart function of these mice is decreased. Further investigation revealed that the Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that are heterozygous for a null p38a gene partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocytes proliferation.Because both the intrauterine environment and the fetal-maternal interface are critical for fetal development and growth, the placental defects need to be separated from those observed in the heart in this study. This separation was accomplished using a cardiac-specific knockout for Akt1. Unexpectedly, the/Mesp1-Cre-mediated, cardiac-specific Akt1 knockout mice appeared normal. Further analysis showed that Akt1 was present at very low levels in the Akt1F/F;Mesp1-Cre+/- mice hearts. This low level was enough to maintain a partial role in the functioning of the heart.Previous study indicated that other Akt isoforms exhibit gene dosage effects relative to Akt1, and we determined that Akt1F/F;Mesp1-Cre+/-;Akt3homo mice had an embryonic lethal phenotype. Further analysis showed that the Akt1F/F;Mesp1-Cre+/-;Akt3homo mice die at about embryonic day 14.5 (E14.5). By E14.5, all Akt1F/F;Mesp1-Cre+/-;Akt3homo mice at E14.5 have congenital heart defects and a thinner myocardium. Cardiac cell proliferation was significantly decreased, which may contribute to the congenital heart defects and thinner myocardium.In conclusion, these results suggest that Akt isoforms play an important role in heart development, potentially in a dosage-dependent manner. Thus, the roles of the Akt isoforms need to be further studied.