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: 8856328
• 负责人: Xun Ai
• 金额: $ 37.18万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856328
• 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; transcription factor; treatment strategy; 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; 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）是最常见的心律不齐，会导致死亡率和明显发病率（例如中风和心力衰竭（HF））的风险增加。 AF的患病率，尤其是持续的AF，随着衰老而急剧增加。但是，由于缺乏对AF的基本分子机制的了解，老年人的药理治疗和预防策略仍然无效。 C-JUN N末端激酶（JNK）是一种应激激活的蛋白激酶，对于包括HF和肥大在内的心血管疾病的发展至关重要。最近的研究表明，JNK在连接下调（CX43）的下调中的重要作用。 CX43是与AF稳定和维护相关的主要心房间隙连接蛋白之一。但是，JNK在AF开发中的作用仍然未知。我们有有趣的初步证据，表明年龄兔子左心房（LA）的JNK激活显着增强，这有助于CX43显着减少，并导致起搏引起的AF的持续时间显着增加。该提案的目的是进一步确定JNK激活在CX43还原中的关键作用，从而损害了细胞 在老年la中耦合并增强AF。目的1是评估JNK激活对CX43减少，细胞解偶联和AF维护的功能影响。我们将使用互补的电生理学（光学映射空间常数，4电极微抑制光谱，细胞染料偶联）和生化测量值，以全面了解JNK诱导的CX43 CX43减少，减少的细胞耦合在完整的LA组织和肌细胞中的细胞耦合受损及其对ITS ITS ITS对AF的影响。这将通过[老年兔子和人类的心脏]和具有JNK激活或失活的心脏特异性JNK转基因（TG）小鼠来实现。目的2是确定JNK诱导的CX43还原的分子机制，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在隔离的rabbit和Jnk tgbit中的孤立性肌细胞中，将揭示JNK TGBIT和JNK TGBIT的重要作用。 减少。这些实验整合了重要的功能测量和基本机械研究。结果将为JNK信号作为新颖的潜力提供重要的见解 老年人预防AF的治疗靶标。我们的长期目标是了解具有HF等心血管疾病的老年心脏中AF发育的分子机制，将在当前建议的结果中大大提高。