The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart.
The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart.
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DOI：
10.1016/j.yjmcc.2017.11.006
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发表时间：
2018-01
影响因子：
5
通讯作者：
Ai X
中科院分区：
文献类型：
--
作者：
Yan J;Thomson JK;Zhao W;Wu X;Gao X;DeMarco D;Kong W;Tong M;Sun J;Bakhos M;Fast VG;Liang Q;Prabhu SD;Ai X
应激激酶c-jun N-末端激酶（JNK）在与心房颤动（AF）发病率增加相关的心脏疾病的发病机制中是关键的，心房颤动是老年人中最常见的心律失常。我们最近发现JNK激活与缝隙连接连接蛋白43（Cx43）的缺失和心房肌促炎性增强有关。然而，缺乏JNK介导的损伤的细胞间耦合（细胞间通讯）在完整的老年心房的直接证据，是证据是否和如何JNK抑制Cx43在老年人心房。人心房样本中JNK活性与Cx43表达减少和年龄增加相关。使用一种独特的技术，光学映射空间常数测量，我们发现，受损的细胞间耦合和减少Cx43与增强激活JNK在完整的老年兔心房。这些JNK相关的改变在自然JNK激活的老年小鼠和心脏特异性诱导型MKK 7 D（JNK上游激活剂）年轻小鼠中得到进一步证实。此外，JNK抑制，使用JNK特异性抑制剂在老年野生型（WT）小鼠和JNK激活剂茴香霉素治疗的年轻WT小鼠或JNK 1/2显性阴性小鼠与基因抑制心脏JNK活性，完全消除这些功能异常。此外，我们首次发现长期JNK激活通过c-jun抑制Cx43基因启动子的转录活性来下调Cx43表达。我们的研究结果表明，JNK是Cx43表达的一个重要调节因子，老年人心房中增强的JNK激活下调Cx43，损害细胞间通讯，促进AF的发展。JNK抑制可能是预防或治疗老年人AF的一种有前途的治疗方法。
The stress kinase c-jun N-terminal kinase (JNK) is critical in the pathogenesis of cardiac diseases associated with an increased incidence of atrial fibrillation (AF), the most common arrhythmia in the elderly. We recently discovered that JNK activation is linked to the loss of gap junction connexin43 (Cx43) and enhanced atrial arrhythmogenicity. However, direct evidence for JNK-mediated impairment of intercellular coupling (cell-cell communication) in the intact aged atrium is lacking, as is evidence for whether and how JNK suppresses Cx43 in the aged human atrium. JNK activity in human atrial samples is correlated with both reduced Cx43 expression and increasing age. Using a unique technique of optical mapping space constant measurement, we found that impaired intercellular coupling and reduced Cx43 were linked to enhanced activation of JNK in intact aged rabbit atria. These JNK-associated alterations were further confirmed in naturally JNK activated aged mice and in cardiac-specific inducible MKK7D (JNK upstream activator) young mice. Moreover, JNK inhibition, using either JNK specific inhibitors in aged wild-type (WT) mice and JNK activator anisomycin-treated young WT mice or JNK1/2 dominant-negative mice with genetically inhibited cardiac JNK activity, completely eliminated these functional abnormalities. Furthermore, we discovered for the first time that long-term JNK activation downregulates Cx43 expression via c-jun suppressed transcriptional activity of the Cx43 gene promoter. Our results demonstrate that JNK is a critical regulator of Cx43 expression, and that augmented JNK activation in aged atria downregulates Cx43 to impair cell-cell communication and promote the development of AF. JNK inhibition may represent a promising therapeutic approach to prevent or treat AF in the elderly.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
10.8
作者：
Bruce AF;Rothery S;Dupont E;Severs NJ
通讯作者：
Severs NJ
影响因子：
37.8
作者：
Oral, H;Scharf, C;Morady, F
通讯作者：
Morady, F
影响因子：
37.8
作者：
Pappone, C;Oreto, G;Alfieri, O
通讯作者：
Alfieri, O
影响因子：
20.1
作者：
Beauchamp, Philippe;Yamada, Kathryn A.;Kleber, Andre G.
通讯作者：
Kleber, Andre G.