Deletion of Akt1 causes heart defects and abnormal cardiomyocyte proliferation

Abstract

The PI3K-PDK1-PKB/Akt (PI3K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase 1; PKB, protein kinase B) signaling pathway plays a critical role in a variety of biological processes including cell survival, growth and proliferation, metabolism and organogenesis. Previously, we generated Akt1-deficient mice and found high neonatal mortality with unknown causes. Here we report that histological analysis of Akt1-deficient embryos and newborns revealed heart defects and decreased cell proliferation. Echocardiographic study of Akt1-deficient mice indicated decreased heart function. Further investigation revealed that Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that were heterozygous for a null p38α partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocyte proliferation. Our study suggests that Akt1 is essential for heart development and function, in part, through suppression of p38MAPK activation.

Why is Heart Rarely Affected by Cancer?

“…Therefore it is postulated that the heart may contain some specific gene which is not expressed or stimulated abnormally in response to any factors such as mutagen. This postulation is in agreement with the echocardiographic study of Akt1 gene deficient mice model which revealed that deletion of Akt1 caused substantial activation of p38MAPK leads to abnormal cardiomyocyte proliferation [7]. Therefore, further genomic study of heart may focus some inputs to analyses the presence of specific gene which prevent abnormal proliferation of cardiac cells.…”

DNA methylation abnormalities in congenital heart disease

“…Disruption of Akt1 in mice causes CHD with a reduction in cell proliferation. 39 Mutations in other genes related to cell growth such as Hes1, or apoptosis such as Alk5, have already been associated to CHD in animal models. Hes1 knockout mouse embryos display defects in proliferation at early developmental stages, which induce a reduction in cardiac neural crest cells and failure to completely extend the outflow tract.…”

Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice

“…The protocols for hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and immunofluorescence (IF) were as described previously (23,27). Briefly, heart samples were first washed with ice-cold phosphate-buffered saline (PBS) and then fixed in 4% paraformaldehyde (PFA) at 4°C.…”

“…The TUNEL (TdT [terminal deoxynucleotidyltransferase]-mediated dUTP nick end labeling) assay was performed as described previously (23,27). Briefly, sections were treated with proteinase K (20 g/ml) and incubated with TdT and biotinylated dUTP.…”