The Stress Response Kinase JNK and Alcohol Evoked Atrial Fibrillation

应激反应激酶 JNK 和酒精诱发心房颤动

• 批准号: 10516469
• 负责人: Xun Ai
• 金额: $ 30.16万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516469
• 关键词: Stress; Response; Kinase; JNK; Alcohol

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.

过量饮酒（短时间内大量饮酒）已被广泛 心房颤动（AF）是临床诊断的最常见的心律失常， 实践尽管迄今为止已经做出了重大努力来减少酗酒，但反复酗酒仍然存在 在全国范围内普遍存在，因此酒精相关性AF的患病率很高。这造成了巨大的 由于昂贵的房颤消融术和消融后房颤复发率高，给我们的社会带来经济负担 如果患者同时患有心血管疾病。不幸的是，目前可用的药物治疗， 由于缺乏对其潜在机制的了解，酒精诱发的AF发生仍然无效。我们 拟议的研究将通过鉴定应激反应c-Jun N末端激酶来填补这一重要的知识空白 (JNK)作为酒精诱发房颤发生的重要调节剂。已知JNK有助于与酒精相关的 细胞死亡和组织损伤。我们最近首次报道激活的JNK在AF底物中是关键的 形成和AF发展。JNK-AF的关系提供了一个逻辑途径，通过它酒精可以 增加房颤倾向。事实上，我们初步的人类和动物研究结果表明，过量饮酒 暴露显著增加JNK活化，其增强钙调蛋白II型激酶（CaMKII，一种众所周知的 促心律失常分子）依赖性肌浆网（SR）Ca泄漏和异常舒张Ca火花/波， 从而增加房性心律失常的倾向。显性失活JNK转基因小鼠 减弱这些酒精引起的异常钙活动。在该提议中，JNK对RyR通道的贡献 功能障碍和异常的钙活动将使用独特的小鼠模型进行解剖， JNK或CaMK II活性或RyR 2单通道功能。将小鼠模型的结果转化为 我们将在人类供体心脏中进行验证研究。我们将使用辅助电生理 方法（完整心房/分离心房肌细胞的电压/Ca双通道光学标测和共焦Ca成像 以及体内AF诱导）和生化技术，以全面了解 通过增加RyR 2介导的SR Ca泄漏（Aim 1），酒精激活的JNK和Ca触发的AF之间的关系。的 酒精诱发的JNK如何改变RyR 2通道功能以增加SR泄漏和火花/波的机制基础 (Aim 2）将详细描述在具有临床症状的小鼠中透化心房肌细胞和单个RyR 2通道的水平。 使用人类供体心脏组织验证适用性。该提案整合了重要的功能测量 和基本的机制研究沿着适当的替代方法。药物干预 限制JNK活性和修饰RyR 2通道功能的药物将作为潜在的治疗选择进行测试， JNK的RyR 2作用也可能增加与其他应激（例如衰老、肥胖、心脏病）相关的心律失常风险。 失败等）。因此，这里定义的潜在机制和测试的治疗干预可能会延长 潜在意义超出酒精相关AF。

项目成果

Holiday Heart Syndrome, Atrial Fibrillation, and RyR2 Antagonist.

• DOI: 10.1097/fjc.0000000000001352
• 发表时间: 2022-11-01
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Yan J;Ai X
• 通讯作者: Ai X

Upregulation of transient receptor potential melastatin 4 (TRPM4) in ventricular fibroblasts from heart failure patients.

• DOI: 10.1007/s00424-021-02525-2
• 发表时间: 2021-03
• 期刊: Pflugers Archiv : European journal of physiology
• 作者: Feng J;Zong P;Yan J;Yue Z;Li X;Smith C;Ai X;Yue L
• 通讯作者: Yue L

The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart.

• DOI: 10.1016/j.yjmcc.2017.11.006
• 发表时间: 2018-01
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Yan J;Thomson JK;Zhao W;Wu X;Gao X;DeMarco D;Kong W;Tong M;Sun J;Bakhos M;Fast VG;Liang Q;Prabhu SD;Ai X
• 通讯作者: Ai X

Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk.

• DOI: 10.1007/s00424-021-02533-2
• 发表时间: 2021-03
• 期刊: Pflugers Archiv : European journal of physiology
• 作者: McKee C;Bare DJ;Ai X
• 通讯作者: Ai X

Serine-threonine protein phosphatase regulation of Cx43 dephosphorylation in arrhythmogenic disorders.

• DOI: 10.1016/j.cellsig.2021.110070
• 发表时间: 2021-10
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Ai X;Yan J;Pogwizd SM
• 通讯作者: Pogwizd SM