Enhanced catecholamine release in mice expressing PKB/SGK-resistant GSK3

Area of Science:

• Physiology
• Molecular Biology
• Cardiovascular Research

Background:

• Glycogen synthase kinase 3 (GSK3) is crucial for cellular functions.
• GSK3 activity is regulated by phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt)/serum and glucocorticoid inducible kinase (SGK) signaling.
• Disruption of this signaling pathway in gene-targeted knockin (KI) mice leads to elevated blood pressure compared to wild-type (WT) mice.

Purpose of the Study:

• To investigate the underlying mechanisms for the increased blood pressure in gsk3 KI mice.
• To elucidate the role of GSK3 signaling in blood pressure and heart rate regulation.
• To determine the impact of disrupted GSK3 signaling on catecholamine release.

Main Methods:

• Blood pressure and heart rate were measured using tail cuff and ECG, respectively.
• Catecholamine levels were quantified via ELISA.
• Urinary vanillylmandelic acid excretion was analyzed using high-performance liquid chromatography.
• Pharmacological blockade of adrenergic receptors and ganglia was performed.

Main Results:

• gsk3 KI mice exhibited significantly higher blood pressure and heart rate than gsk3 WT mice.
• Alpha- and beta-adrenergic blockers, as well as ganglion blockers, reduced blood pressure and heart rate more effectively in gsk3 KI mice.
• Plasma epinephrine and norepinephrine concentrations, along with urinary vanillylmandelic acid, were elevated in gsk3 KI mice.
• The observed differences between genotypes were largely abolished after pharmacological interventions.

Conclusions:

• PKB/Akt/SGK-dependent GSK3 signaling plays a novel role in regulating catecholamine release.
• Disruption of this signaling pathway contributes to hypertension through increased sympathetic nervous system activity.
• GSK3 is a potential therapeutic target for managing blood pressure and related cardiovascular conditions.