The pre-disposition for atrial fibrillation (AF) increases with age and in the presence of other cardiovascular morbidities such as hypertension and hypertrophy. This makes AF the most common sustained arrhythmia with a high morbidity and mortality based on thromboembolic events and stroke. Our new preliminary data demonstrate for the first time that the p21-activated kinase (Pak1) is down-regulated in the atria of AF patients, a canine model of chronic AF and that Pak1 down-regulation is mimicked in an in vitro AF model. We show that loss of Pak1 activity (Pak1-/- mouse) increases the inducibility of AF in mice and facilitates AF like tissue remodeling. Our recently published and preliminary data support that Pak1 is a negative regulator of Rac1 dependent, NADPH oxidase 2 (NOX2)-induced, ROS production. For the first time we now present evidence, that restoration of Pak1 activity in a canine AF model can antagonize ROS production as well as basal and agonist induced triggered activity. Based on this experimental evidence we will test the novel hypothesis that stimulation of Pak1 activity in the etiology of AF decreases the propensity for atrial arrhythmia by negative regulation of NOX2 and attenuation of tissue remodeling. The hypothesis will be tested in three specific aims where we will determine 1. role of Pak1 in the development of AF triggered activity and tissue remodeling; 2. mechanism by which Pak1 regulates NOX2 activity thereby attenuating atrial arrhythmic activity and remodeling and 3. the mechanism by which Pak1 stimulation attenuates arrhythmic activity in AF models. After completion of these aims we will have identified a novel mechanism to antagonize Rac1 dependent NOX2/ROS production, identified the mechanism by which a basal increase in NOX2 enhances arrhythmic activity, and demonstrated a mechanism by which restoration of Pak1 activity represents a promising new therapeutic approach in the treatment of AF.

Public Health Relevance

Atrial fibrillation is the most common cardiac arrhythmia and treatment amounts to an estimated $ 6.65 billion annually in healthcare costs in the USA. Remodeling of the atrial tissue facilitates the development of re- entrant excitations and reduces the success of surgical ablation procedures, which are currently the predominating form of treatment. We identify a novel physiological mechanism to attenuate ROS production, one of the main driving forces for atrial arrhythmia and remodeling and thereby identify an important new approach to suppress arrhythmic triggers and remodeling opening the way for the development of a new therapeutic strategy in the future treatment of AF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Shi, Yang
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Rush University Medical Center
Schools of Medicine
United States
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