The Stress Response Kinase JNK and Alcohol Evoked Atrial Fibrillation

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Excessive binge alcohol intake (large amount of drinking within a short period of time) has been widely recognized as a high risk factor for atrial fibrillation (AF), which is the most common arrhythmia in diagnosed clinical practice. Although significant efforts have been made to date to reduce binge drinking, repeated binge remains prevalent nationwide and consequently the prevalence of alcohol associated AF is high. This causes a tremendous economic burden on our society due to expensive AF ablation procedures and high rate of recurrent AF after ablation if patients have coexisting cardiovascular diseases. Unfortunately, currently available pharmacological therapies for alcohol-provoked AF genesis remain ineffective due to a lack of understanding of its underlying mechanisms. Our proposed studies would fill this important knowledge gap by identifying stress-response c-Jun N-terminal kinase (JNK) as an important regulator in alcohol-provoked AF genesis. JNK is known to contribute to alcohol associated cell death and tissue injury. We have recently reported for the first time that activated JNK is critical in AF substrate formation and AF development. This JNK-AF relationship provides a logical pathway through which alcohol may increase propensity for AF. Indeed, our preliminary human and animal results indicate that excessive binge alcohol exposure dramatically increases JNK activation, which enhances calmodulin type II kinase (CaMKII, a well-known pro-arrhythmia molecule) dependent sarcoplasmic reticulum (SR) Ca leak and aberrant diastolic Ca sparks/waves, thus increasing propensity for atrial arrhythmias. Inactivated JNK transgenic mice with dominant negative mutations attenuated these alcohol-provoked abnormal Ca activities. In this proposal, the JNK contribution on RyR channel dysfunction and abnormal Ca activities will be dissected using unique mouse models with genetically manipulated JNK or CaMKII activities or RyR2 single channel function. To potentially translate results from mouse models to humans, we will perform validation studies in human donor hearts. We will use complementary electrophysiological approaches (voltage/Ca dual channel optical mapping and confocal Ca imaging in intact atria/isolated atrial myocytes as well as in vivo AF induction) and biochemical techniques to gain a comprehensive picture of the relationship between alcohol-activated JNK and Ca-triggered AF via increased RyR2-mediated SR Ca leak (Aim1). The mechanistic basis of how alcohol-evoked JNK alters RyR2 channel function to increase SR leak and sparks/waves (Aim 2) will be detailed at the levels of permeabilized atrial myocytes and single RyR2 channels in mice with clinical applicability verified using human donor heart tissue. This proposal integrates important functional measurements and fundamental mechanistic studies along with appropriate alternative approaches. Pharmacological interventions that limit JNK activity and modify RyR2 channel function will be tested as potential therapeutic options to prevent and/or treat AF. JNK’s RyR2 action may also add to arrhythmia risk tied to other stresses (e.g. aging, obesity, heart failure, etc.). Thus, the underlying mechanism defined and therapeutic interventions tested here may extend the potential significance beyond alcohol associated AF.