PKCβ/NF-κB pathway in diabetic atrial remodeling

Area of Science:

• Cardiovascular Research
• Diabetology
• Molecular Biology

Background:

• Diabetes mellitus is associated with atrial remodeling, a process implicated in atrial fibrillation (AF).
• Nuclear factor-kappa B (NF-κB) and transforming growth factor-beta (TGF-β) signaling pathways are key mediators of this atrial remodeling.
• The role of protein kinase C-beta (PKCβ) in hyperglycemia-induced activation of these pathways remains to be fully elucidated.

Purpose of the Study:

• To investigate the dependency of hyperglycemia-induced NF-κB/TGF-β expression on PKCβ.
• To test the efficacy of selective PKCβ inhibition using ruboxistaurin (RBX) in mitigating NF-κB/TGF-β expression and atrial remodeling in a rat model of diabetes.
• To evaluate the impact of PKCβ inhibition on the inducibility of atrial fibrillation in diabetic rats.

Main Methods:

• Streptozotocin (STZ)-induced diabetic rat model was used to study atrial remodeling.
• Mouse atrial cardiomyocytes (HL-1 cells) were cultured under high-glucose conditions with or without PKCβ inhibition (using small interference RNA or ruboxistaurin).
• Expression levels of key proteins in the NF-κB/TGF-β pathway (NF-κBp65, p-IκB, P38MARK, TNF-α, TGF-β, Cav1.2, NCX) and atrial fibrillation inducibility were assessed.

Main Results:

• Hyperglycemia in diabetic rats and in cultured cardiomyocytes led to increased PKCβ activation and subsequent upregulation of NF-κB and TGF-β signaling.
• Treatment with ruboxistaurin (RBX) significantly decreased the expression of NF-κBp65, p-IκB, P38MARK, TNF-α, TGF-β, Cav1.2, and NCX proteins in STZ-induced diabetic rats.
• PKCβ inhibition also reduced the inducibility of atrial fibrillation in diabetic rats and decreased high-glucose-induced NF-κB and extracellular signal-related kinase activation in HL-1 cells.

Conclusions:

• Hyperglycemia-induced atrial remodeling and increased NF-κB/TGF-β signaling in diabetes are dependent on PKCβ activation.
• Selective pharmacological inhibition of PKCβ using ruboxistaurin effectively reduces NF-κB/TGF-β pathway activation and prevents abnormal atrial remodeling in diabetic rats.
• Targeting PKCβ represents a promising therapeutic strategy to reduce the incidence of atrial fibrillation in diabetic patients.