The role of P21-activated kinase (Pak1) in sinus node function.

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cardiac Electrophysiology

Background:

• Sinoatrial node (SAN) dysfunction (SND) and atrial fibrillation (AF) often coexist, with SND patients having a 4.2-fold higher risk of new-onset AF.
• In atrial muscle, reduced p21-activated kinase 1 (Pak1) activity elevates AF risk via increased reactive oxygen species (ROS) production.
• The role of Pak1-mediated ROS regulation in SAN function remains unclear.

Purpose of the Study:

• To investigate the role of Pak1 in regulating SAN activity and heart rate.
• To test the hypothesis that Pak1 activity maintains SAN function by modulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channel expression.

Main Methods:

• Quantified intrinsic sinus rhythm in wild-type (WT) and Pak1-deficient (Pak1-/-) mice using in vivo and ex vivo Langendorff perfusion methods.
• Assessed the contribution of the Ca2+ clock and membrane clock (using Ivabradine, an HCN channel blocker) to pacemaker activity.
• Measured HCN4 expression in atrial tissue and evaluated rescue strategies including class II HDAC inhibition, ROS scavenging, and ERK1/2 inhibition.

Main Results:

• Pak1-/- mice exhibited significantly reduced heart rate compared to WT mice, both in vivo and in isolated hearts.
• The difference in SAN activity between genotypes was abolished by Ivabradine, indicating a critical role for HCN channels.
• Reduced HCN4 expression was observed in Pak1-/- atria, and this deficit was reversible with LMK235, TEMPOL, or SCH772984.
• No sex-specific differences in Pak1-dependent SAN regulation were found.

Conclusions:

• Pak1 plays a crucial role in maintaining SAN function and heart rate, primarily through regulating HCN channel expression.
• Pak1 acts as a regulator of class II histone deacetylases (HDACs) and influences ROS and ERK1/2 signaling pathways.
• Targeting Pak1 represents a potential therapeutic strategy for mitigating SAN bradycardia and reducing susceptibility to atrial fibrillation.