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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
Deletion of PDK1 causes cardiac sodium current reduction in mice
Zhonglin Han1, Yu Jiang1, Yuqing Yang1
1Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Background:
The AGC protein kinase family regulates multiple cellular functions. 3-phosphoinositide-dependent protein kinase-1 (PDK1) is involved in the pathogenesis of arrhythmia, and its downstream factor, Forkhead box O1 (Foxo1), negatively regulates the expression of the cardiac sodium channel, Nav1.5. Mice are known to die suddenly after PDK1 deletion within 11 weeks, but the underlying electrophysiological bases are unclear. Thus, the aim of this study was to investigate the potential mechanisms between PDK1 signaling pathway and cardiac sodium current.
Methods And Results:
Using patch clamp and western blotting techniques, we investigated the role of the PDK1-Foxo1 pathway in PDK1 knockout mice and cultured cardiomyocytes. We found that PDK1 knockout mice undergo slower heart rate, prolonged QRS and QTc intervals and abnormal conduction within the first few weeks of birth. Furthermore, the peak sodium current is decreased by 33% in cells lacking PDK1. The phosphorylation of Akt (308T) and Foxo1 (24T) and the expression of Nav1.5 in the myocardium of PDK1-knockout mice are decreased, while the nuclear localization of Foxo1 is increased. The role of the PDK1-Foxo1 pathway in regulating Nav1.5 levels and sodium current density was verified using selective PDK1, Akt and Foxo1 inhibitors and isolated neonatal rat cardiomyocytes.
Conclusion:
These results indicate that PDK1 participates in the dysregulation of electrophysiological basis by regulating the PDK1-Foxo1 pathway, which in turn regulates the expression of Nav1.5 and cardiac sodium channel function.
Insights
3-phosphoinositide-dependent protein kinase-1 (PDK1) deficiency impairs cardiac sodium channel function via the PDK1-Foxo1 pathway, leading to electrophysiological abnormalities and sudden death in mice.
Area of Science:
- Cardiology
- Molecular Biology
- Electrophysiology
Background:
- The AGC protein kinase family, including PDK1, plays a role in cellular functions.
- PDK1 and its downstream factor Foxo1 are implicated in arrhythmia pathogenesis.
- PDK1 deletion in mice causes sudden death, but the electrophysiological basis is unknown.
Purpose of the Study:
- To investigate the electrophysiological mechanisms linking the PDK1 signaling pathway to cardiac sodium current.
- To elucidate the role of the PDK1-Foxo1 pathway in regulating cardiac sodium channel Nav1.5.
Main Methods:
- Patch clamp and western blotting techniques were used in PDK1 knockout mice and cultured cardiomyocytes.
- Selective inhibitors of PDK1, Akt, and Foxo1 were employed.
- Neonatal rat cardiomyocytes were utilized for verification.
Main Results:
- PDK1 knockout mice exhibited bradycardia, prolonged QRS and QTc intervals, and abnormal conduction.
- Peak sodium current density decreased by 33% in PDK1-deficient cells.
- PDK1 deficiency reduced Akt and Foxo1 phosphorylation, decreased Nav1.5 expression, and increased Foxo1 nuclear localization.
Conclusions:
- PDK1 regulates cardiac sodium channel function and expression through the PDK1-Foxo1 pathway.
- This pathway is critical for maintaining normal cardiac electrophysiology.
- Dysregulation of the PDK1-Foxo1 pathway contributes to cardiac electrical abnormalities.
