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: 8398893
• 负责人: Xun Ai
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398893
• 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. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common arrhythmia with an increased risk of mortality and a significant morbidity (e.g. stroke, heart failure) in aging population. This proposal is to investigate the pivotal role of c-jun N-terminal kinase (JNK) in connexin43 suppression that in turn enhances AF in aged atria. The results will provide an important basis for further understanding JNK signaling in the development of AF in aged hearts with co-existing cardiovascular disease (e.g. heart failure), and ultimately developing novel effective therapeutic strategies to prevent AF and/or enhance treatment of AF in the elderly.

描述(由申请人提供)：房颤(AF)是最常见的心律失常，会增加死亡和严重发病率(如中风和心力衰竭(HF))的风险。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氨基末端激酶(JNK)是一种应激激活的蛋白激酶，在包括心力衰竭和肥厚在内的心血管疾病的发生发展中起关键作用。最近的研究表明，JNK在细胞间隙连接蛋白43(Cx43)下调中起重要作用。Cx43是与房颤稳定和维持相关的主要心房缝隙连接蛋白之一。然而，JNK在房颤发生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)JNK活性显著增强，有助于显著减少Cx43，并相关地显著延长起搏诱发的房颤持续时间。这项建议的目的是进一步确定JNK激活在Cx43还原中的关键作用，Cx43还原进而损害细胞 耦合和增强老年洛杉矶的房颤。目的1是评估JNK激活对Cx43还原、细胞解偶联和房颤维持的功能影响。我们将使用互补的电生理(光学标测空间常数、4电极微阻抗谱、细胞染料偶联)和生化测量来全面了解JNK诱导的Cx43减少、完整LA组织和心肌细胞的细胞偶联受损之间的关系及其对体内房颤发生的影响。这将在[老龄兔和人心脏]和心脏特异性JNK转基因(TG)小鼠身上实现，这些小鼠具有JNK激活或失活。目的2探讨JNK诱导衰老兔和人LA心肌细胞Cx43基因表达下调和Cx43蛋白降解的分子机制。在老年兔和JNK TG小鼠分离的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还原中的关键作用。这些实验结合了重要的功能测量和基础机制研究。这些结果将为JNK信号作为一种新型信号的潜力提供重要的见解 老年房颤防治的治疗靶点。我们的长期目标，即了解老年心脏并发心力衰竭等心血管疾病时房颤发生的分子机制，将极大地促进目前这项提议的结果。 公共卫生相关性：房颤(房颤)是最常见的心律失常，在老龄化人口中具有更高的死亡率和显著的发病率(如中风、心力衰竭)。本研究旨在探讨c-jun氨基末端激酶(JNK)在抑制连接蛋白43进而增强老年心房颤动中的关键作用。这些结果将为进一步了解JNK信号在老年心脏伴发心血管疾病(如心力衰竭)发生房颤的过程中的作用提供重要基础，并最终开发新的有效治疗策略来预防和/或加强老年人房颤的治疗。