Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology

Abstract

Holiday Heart Syndrome (HHS) is cardiac arrhythmia induced by binge alcohol consumption, a drinking pattern affects 38 million adults in our society. Atrial fibrillation (AF) is the most frequently diagnosed arrhythmia in HHS and causes significant morbidity and mortality. Despite the intensive prevention effort nationwide, the binge drinking population keeps rising. However, no effective treatment strategies are available for binge drinking induced AF due to the unknown underlying mechanisms. In this thesis, I aim to elucidate the mechanisms of binge alcohol-promoted atrial arrhythmogenicity by using a mouse model of repeated binge alcohol exposure established in the Ai Lab.

The Ai Lab has recently discovered that the activation of stress-response kinase c-Jun N-terminal kinase (JNK) plays an essential role in atrial arrhythmogenicity. Interestingly, previous research also documented that alcohol promotes JNK activation in non-atrial tissue. However, it is unknown whether JNK plays a role in binge alcohol-induced atrial arrhythmogenicity. In this thesis, I found increased JNK activation in repeated binge alcohol-exposed mouse/rabbit atria. In addition, abolishing JNK pathway with dominant negative JNK overexpression in the heart (JNK1/2dn mice) successfully suppressed binge alcohol-promoted atrial arrhythmia.

Aberrant Ca2+ activities, especially Ca2+ waves, play a pivotal role in arrhythmogenicity. Ca2+/calmodulin-dependent kinase II (CaMKII) is a well-established arrhythmogenic molecule that regulates multiple cardiac Ca2+ handling proteins. Previous research has shown that CaMKII-dependent phosphorylation of ryanodine receptor (RyR), the main Ca2+ release channel on the sarcoplasmic reticulum (SR), results in enhanced SR Ca2+ leak and the rise of Ca2+ waves. SR Ca2+ overload has also been shown to sensitize RyR and promote diastolic SR Ca2+ leak. However, it is unknown whether Ca2+ mishandling plays a vital role in binge drinking-induced atrial arrhythmia. In this thesis, I found an increased frequency of Ca2+ waves in atrial tissue from binge alcoho- exposed mice, while abolishing the JNK pathway in JNK1/2dn mice precluded the Ca2+ wave occurrence. CaMKII activation and CaMKII-dependent RyR phosphorylation were both enhanced after alcohol exposure. On the other hand, a single dose of CaMKII inhibitor (KN93) treatment after binge alcohol exposure reversed the atrial Ca2+ waves and atrial arrhythmogenicity in WT mice. Alcohol-treated atrial myocytes (HL-1 cells) revealed enhanced diastolic SR Ca2+ leak, while suppressing JNK or CaMKII both alleviated the SR Ca2+ leak, further indicating alcohol induced JNK/CaMKII contributes to arrhythmogenic Ca2+ mishandling. Further studies showed alcohol exposure promotes CaMKII activation in a JNK-dependent manner, but not via direct oxidation of redox-sensitive amino acid sites (Met280/281) on CaMKII. Besides CaMKII-dependent RyR phosphorylation, enhanced SR Ca2+ load can also promote SR Ca2+ leak via sensitizing the SR luminal Ca2+ sensor of RyR. I found increased SR Ca2+ load in alcohol-treated atrial myocytes via a JNK-dependent yet CaMKII-independent mechanism. Ablating SR Ca2+ luminal sensor with RyR E4872Q+/- mutation alleviated the binge alcohol or JNK activation-induced increase in Ca2+ waves and atrial arrhythmogenicity.

In conclusion, the key findings of this thesis work are: 1) repeated binge alcohol leads to enhanced activation of stress-response kinase; 2) JNK2 phosphorylates CaMKII, a pro-arrhythmic molecule, and promotes CaMKII-dependent diastolic SR Ca leak via increased RyR channel activity; 3) JNK2 elevates SR Ca load via JNK-enhanced SERCA uptake. Findings in this work suggest that JNK inhibition could be a therapeutic strategy for binge alcohol prompted atrial arrhythmias.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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