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: 8791438
• 负责人: Xun Ai
• 金额: $ 0.26万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791438
• 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）：房颤（AF）是最常见的心律失常，可导致死亡率和严重发病率（如卒中和心力衰竭（HF））风险增加。随着年龄的增长，房颤的患病率，特别是持续性房颤的患病率急剧增加。然而，药物治疗和预防策略在老年人仍然无效，由于缺乏了解的潜在的分子机制AF。c-Jun N-末端激酶（JNK），应激激活的蛋白激酶，是关键的心血管疾病，包括HF和肥大的发展。最近的研究表明JNK在下调连接蛋白43（Cx43）中起重要作用。Cx43是与AF稳定和维持相关的主要心房缝隙连接蛋白之一。然而，JNK在AF发展中的作用仍然未知。我们有有趣的初步证据表明，在老年兔左心房（LA）显著增强的JNK激活有助于显著的Cx43减少和起搏诱导的AF持续时间的显著增加。本建议的目的是进一步确定JNK激活在Cx43减少中的关键作用，进而损害细胞凋亡。 偶联并增强老年LA中的AF。目的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，以获得JNK诱导的Cx43减少，受损的细胞耦合在完整的LA组织和肌细胞之间的关系，以及其对AF发展的影响在体内的全面图片。这将通过[老年兔和人心脏]和JNK活化或失活的心脏特异性JNK转基因（Tg）小鼠实现。目的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LA肌细胞中]。一系列的体外基因转移实验中分离的心房肌细胞从老年兔和JNK Tg小鼠将揭示的关键作用，JNK异构体在Cx43的减少。这些实验整合了重要的功能测量和基本的机理研究。这些结果将为JNK信号转导作为一种新的治疗方法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中AF发展的分子机制，同时存在心血管疾病，如HF，当前提案的结果将大大推进。