Pole And Mechanism Of PDK1in Cardiovascular Development

The role of PI3k/PDK1/Akt pathway in cardiac system was first revealed by the pioneering study performed by Walsh and colleagues which documented Akt's function to promote cardiomyocyte survival in vivo. Shortly after. several groups reported almost simultaneously. cardiac hypertrophy and failure in transgenic mice with Akt overexpression in cardiomyocytes. Afterwards. PI3k/PDK1/Akt pathway's involvement in embryonic development has been unveiled along with the generation and characterization of Akt individual knockout mice and subsequent compound Akt deletion mice. We first reported a heart developmental defect in Akt1/3 double knockout mice, which is in consistency with the earlier work performed in Dario Alessi's group showing severe cardiac phenotype in PDK (phosphoinositide-dependent kinase 1) germ-line deletion mice. One essential downstream signaling pathway of receptor tyrosine kinases (RTKs). such as vascular endothelial growth factor receptor (VEGFR) and the Tie2 receptor. is the phosphoinositide-3 kinase (PI3K)-phosphoinositide-dependent protein kinase 1 (PDK1)-Akt/protein kinase B (PKB) cascade that plays a criticalrole in development and tumorigenesis. In the past decade. the function of PI3k/PDKl pathway in heart hypertrophy and cardiac protection has been extensively investigated while PDK1's role in heart development is much less studied. The aim of present study was to show the role and mechanism of PDK 1 in cardiovascular development.Here, we deleted PDK1 specifically in endothelial cells in mice. These mice displayed hemorrhage and hydropericardium and died at approximately embryonic day 11.5 (El1.5). Histological analysis revealed defective vascular remodeling and development and disrupted integrity between the endothelium and trabeculae/ myocardium in the heart. The atrioventricular canal (AVC) cushion and valves failed to form, indicating a defect in epithelial-mesenchymal transition (EMT). together with increased endothelial apoptosis. Consistently, ex vivo AVC explant culture showed impeded mesenchymal outgrowth. Snail protein was reduced and was absent from the nucleus in AVC cells. Delivery of the Snail S6A mutant to the AVC explant effectively rescued EMT defects. Furthermore. adenoviral Akt delivery rescued EMT defects in AVC explant culture, and deletion of PTEN delayed embryonic lethality of PDK1 endothelial deletion mice by 1 day and rendered normal development of the AVC cushion in the PDK1-deficient heart.Taken together. these results have revealed an essential role of PDK1 in cardiovascular development through activation of Akt and Snail. The data presented here could be promising for therapeutic applications. In the future. it will be helpful to modulate Akt signaling to improve cardiovascular complications in human patients.