P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress...

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Mitochondrial Biology

Background:

• Ventricular arrhythmias are a clinical challenge, often linked to cardiac adrenergic stress and hypertrophy.
• The role of P21-activated kinase 2 (Pak2) in regulating cardiac electrical stability under stress is not well understood.

Purpose of the Study:

• To investigate the anti-arrhythmic effects of Pak2 in murine models of cardiac stress and hypertrophy.
• To elucidate the molecular mechanisms underlying Pak2's influence on cardiac function and arrhythmia susceptibility.

Main Methods:

• Utilized cardiomyocyte-specific Pak2 knockout (Pak2^cko) and overexpression (Pak2^ctg) murine models.
• Induced cardiac stress via acute adrenergic stimulation and chronic transverse aortic constriction (TAC).
• Performed cellular electrophysiology, optical mapping, Ca²⁺ transient analysis, electron microscopy, and proteomic/phosphoproteomic analyses.

Main Results:

• Pak2^cko hearts exhibited increased ventricular arrhythmias, prolonged action potential durations, and altered Ca²⁺ handling, particularly after TAC.
• Pak2 deficiency was associated with mitochondrial dysfunction, oxidative stress, reduced ATP synthesis, and elevated NOX4 levels in stressed hearts.
• Pak2 overexpression and activation (JB2019A) ameliorated these detrimental effects, improving cardiac function and reducing arrhythmias.

Conclusions:

• Pak2 activation confers protection against ventricular arrhythmias induced by cardiac stress and hypertrophy.
• Pak2 plays a critical role in maintaining mitochondrial integrity and function under stress.
• Pak2 represents a promising therapeutic target for managing stress- and hypertrophy-induced ventricular arrhythmias.