JNK Suppression of Connexin43 Enhances Atrial Fibrillation in Aged Atria

JNK 抑制 Connexin43 会增强老年心房的心房颤动

• 批准号: 8711549
• 负责人: Xun Ai
• 金额: $ 38.18万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-03 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711549
• 关键词: Address; Aging; Arrhythmia; Atherosclerosis; Atrial Fibrillation; Attention; Attenuated; Biochemical; Biological Assay; Cardiac; Cardiovascular Diseases; Cells; Connexin 43; Connexins; Coupling; Development; Dominant-Negative Mutation; Down-Regulation; Dyes; Elderly; Electrodes; Elements; Exhibits; FOS gene; Gap Junctions; Gene Expression; Gene Transfer; Genes; Genetic; Goals; Grant; Health; Heart; Heart Atrium; Heart failure; Human; Hypertrophy; In Vitro; JUN gene; Knock-out; Knockout Mice; Lead; Left atrial structure; Link; MAP Kinase Gene; MAPK8 gene; MAPK9 gene; Maintenance; Maps; Measurement; Mediating; Messenger RNA; Methods; Molecular; Morbidity - disease rate; Mus; Muscle Cells; N-terminal; Optics; Oryctolagus cuniculus; Pharmacological Treatment; Phosphorylation; Phosphotransferases; Preparation; Prevalence; Prevention; Prevention strategy; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-jun; Resistance; Risk; Role; SP600125; Series; Serine; Signal Transduction; Site; Stroke; Techniques; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Transgenic Mice; Ubiquitin; Ventricular; Wild Type Mouse; aged; aging population; base; design; electric impedance; expectation; gene repression; improved; in vivo; indexing; innovation; insight; kinase inhibitor; link protein; monolayer; mortality; new therapeutic target; novel; prevent; protein degradation; research study; response; stress activated protein kinase; stress-activated protein kinase 1; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common arrhythmia and causes an increased risk of mortality and significant morbidity (such as stroke and heart failure (HF)). The prevalence of AF, especially persistent AF, increases dramatically with aging. However, pharmacological treatment and prevention strategies in the elderly remain ineffective due to a lack of understanding of underlying molecular mechanisms of AF. The c-Jun N-terminal kinase (JNK), a stress-activated protein kinase, is critical in the development of cardiovascular diseases including HF and hypertrophy. Recent studies showed an important role of JNK in downregulation of connexin43 (Cx43). Cx43 is one of the major atrial gap junctional proteins linked to AF stabilization and maintenance. However, the role of JNK in AF development remains unknown. We have intriguing preliminary evidence indicating that significantly enhanced JNK activation in aged rabbit left atria (LA) contributes to marked Cx43 reduction and associated dramatic increase in duration of pacing-induced AF. The objective of this proposal is to further determine the pivotal role of JNK activation in Cx43 reduction that in turn impairs cell coupling and enhances AF in aged LA. Aim 1 is to assess the functional impact of JNK activation on Cx43 reduction, cell uncoupling and AF maintenance. We will use complementary electrophysiological (optical mapping space constant, 4-electrode microimpedance spectra, cell dye coupling) and biochemical measurements to gain a comprehensive picture of the relationship between JNK-induced Cx43 reduction, impaired cell-coupling in intact LA tissue and myocytes and its impact on AF development in vivo. This will be achieved with [aged rabbit and human hearts,] and cardiac specific JNK transgenic (Tg) mice with JNK activation or inactivation. Aim 2 is to identify molecular mechanisms of JNK-induced Cx43 reduction including Cx43 gene downregulation and Cx43 protein degradation [in aged rabbit and human LA myocytes.] A series of in vitro gene transfer experiments in isolated atrial myocytes from both aged rabbit and JNK Tg mice will reveal the critical role of JNK isoforms in Cx43 reduction. These experiments integrate important functional measurements and fundamental mechanistic studies. The results will provide important insights into the potential of JNK signaling as a novel therapeutic target for AF prevention and treatment in the elderly. Our long-term goal, understanding the molecular mechanism of AF development in aged hearts with co-existing cardiovascular diseases such as HF, will be greatly advanced by the results of the current proposal.

描述（由申请人提供）：心房颤动 (AF) 是最常见的心律失常，会导致死亡风险增加和显着发病率（例如中风和心力衰竭 (HF)）。房颤（尤其是持续性房颤）的患病率随着年龄的增长而急剧增加。然而，由于缺乏对房颤潜在分子机制的了解，老年人的药物治疗和预防策略仍然无效。 c-Jun N 末端激酶 (JNK) 是一种应激激活蛋白激酶，在心力衰竭和肥厚等心血管疾病的发展中至关重要。最近的研究表明 JNK 在连接蛋白 43 (Cx43) 下调中发挥重要作用。 Cx43 是与 AF 稳定和维持相关的主要心房间隙连接蛋白之一。然而，JNK 在 AF 发展中的作用仍不清楚。我们有有趣的初步证据表明，老年兔左心房 (LA) 中 JNK 激活显着增强，导致 Cx43 显着减少，并导致起搏引起的 AF 持续时间显着增加。该提案的目的是进一步确定 JNK 激活在 Cx43 减少中的关键作用，从而损害细胞 耦合并增强老年 LA 中的 AF。目标 1 是评估 JNK 激活对 Cx43 减少、细胞解偶联和 AF 维持的功能影响。我们将使用互补的电生理学（光学映射空间常数、4 电极微阻抗谱、细胞染料耦合）和生化测量来全面了解 JNK 诱导的 Cx43 减少、完整 LA 组织和肌细胞中细胞耦合受损及其对体内 AF 发展的影响之间的关系。这将通过[老年兔子和人类心脏]以及具有 JNK 激活或失活的心脏特异性 JNK 转基因 (Tg) 小鼠来实现。目标 2 是确定 JNK 诱导的 Cx43 减少的分子机制，包括 Cx43 基因下调和 Cx43 蛋白降解（在老年兔和人类 ​​LA 肌细胞中）。在老年兔和 JNK Tg 小鼠的分离心房肌细胞中进行的一系列体外基因转移实验将揭示 JNK 亚型在 Cx43 中的关键作用 减少。这些实验整合了重要的功能测量和基本机制研究。这些结果将为 JNK 信号传导作为一种新型药物的潜力提供重要的见解。 老年人房颤预防和治疗的治疗目标。我们的长期目标是了解老年心脏与心力衰竭等心血管疾病共存的房颤发展的分子机制，当前提案的结果将大大推进这一目标。