JNK Suppression of Connexin43 Enhances Atrial Fibrillation in Aged Atria

描述（由申请人提供）：心房颤动（AF）是最常见的心律失常，可导致死亡和显著发病率（如中风和心力衰竭（HF））的风险增加。房颤的患病率，尤其是持续性房颤，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，老年房颤的药物治疗和预防策略仍然无效。c-Jun n -末端激酶（JNK）是一种应激激活的蛋白激酶，在心衰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connexin43 （Cx43）下调中起重要作用。Cx43是心房间隙连接蛋白之一，与心房颤动的稳定和维持有关。然而，JNK在AF发展中的作用尚不清楚。我们有有趣的初步证据表明，老龄兔左心房（LA）中JNK激活的显著增强有助于显著的Cx43减少和相关的起搏诱导AF持续时间的急剧增加。本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

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.