Deletion of PDK₁ Caused Cardiac Malmorphogenesis and Heart Defects Due to Profound Protein Phosphorylation Changes...

Area of Science:

• Cardiovascular Biology
• Molecular Signaling
• Developmental Biology

Background:

• Phosphoinositide-dependent protein kinase-1 (PDK1) is a key regulator in cellular signaling pathways.
• PDK1 plays a vital role in embryonic cardiac development and postnatal cardiac remodeling.
• Complete germline knockout of PDK1 results in embryonic lethality due to failed heart development.

Purpose of the Study:

• To investigate the temporal and spatial roles of PDK1 in cardiac development and disease.
• To characterize the relevance of PDK1 deletion in heart tissue to congenital heart disease (CHD).
• To elucidate the underlying molecular mechanisms of PDK1-mediated cardiac dysfunction.

Main Methods:

• Conditional knockout of PDK1 in cardiac tissue using different Cre-driver lines (Nkx2.5-cre, Mef2c^SHF-cre, αMHC-cre).
• Phenotypic analysis of resulting mouse models, including assessment of cardiac structure and function.
• Protein analysis to evaluate signaling pathway activation and disruption (PI3K, ERK, AKT, GSK3, S6K, S6, SHP2).

Main Results:

• Deletion of PDK1 using Nkx2.5-cre led to prominent pulmonic stenosis.
• Ablation of PDK1 with Mef2c^SHF-cre resulted in severe hypoplasia of the second heart field (SHF).
• αMHC-cre mediated deletion of PDK1 caused dilated heart disease, with altered phosphorylation of AKT, S6K, and GSK3, and activation of PI3K and ERK pathways.
• Elevated SHP2 membrane localization and phosphorylation at Tyr542 suggested SHP2 involvement in PDK1 disruption.

Conclusions:

• Conditional deletion of PDK1 in the heart leads to distinct congenital heart defects, highlighting its critical roles in cardiac development.
• Disruption of PDK1 signaling impacts key pathways including PI3K/AKT and MAPK/ERK, affecting cardiac homeostasis.
• SHP2 appears to be a key mediator in the cardiac dysfunction observed upon PDK1 ablation.