Age-dependent increase in c-Jun N-terminal kinase-2 activity: does this help to understand Ca2+-calmodulin-dependent protein-kinase II-mediated atrial arrhythmogenesis in human atrial fibrillation?
Age-dependent increase in c-Jun N-terminal kinase-2 activity: does this help to understand Ca2+-calmodulin-dependent protein-kinase II-mediated atrial arrhythmogenesis in human atrial fibrillation?
复制标题
c-Jun N 末端激酶 2 活性随年龄增加：这是否有助于理解人房颤中 Ca2-钙调蛋白依赖性蛋白激酶 II 介导的房性心律失常发生？
DOI：
10.1093/cvr/cvy037
复制
发表时间：
2018
影响因子：
10.8
通讯作者：
Lorenz,Kristina
中科院分区：
文献类型：
--
作者：
Dobrev,Dobromir;Lorenz,Kristina
心房颤动（AF）是最常见的心律失常，其患病率随年龄增长而显著增加，并与大量发病率和死亡率相关，心力衰竭恶化和血栓栓塞事件是最突出的并发症。尽管我们对促进AF维持和进展的潜在分子机制的理解取得了巨大进展，但目前的药物治疗选择仅中度有效，并且具有严重的副作用，包括促心律失常。因此，对于具有增加的有效性和改善的安全性特征的新型药物选择存在明显未满足的需求。对AF病理生理学的更好理解有望促进这一发展，并且越来越多的证据强调了异常Ca 2+处理和增加的Ca 2 +-钙调素非依赖性蛋白激酶II（CaMKII）活性在AF病理生理学中的核心作用。1 CaMKII调节多个离子通道、Ca 2+处理和肌丝蛋白，并过表达4-6 CaMKII上调通过调节电、Ca 2+处理和结构重塑的多个要素促进心房肌的发生，1将异常CaMKII定位为AF促进心房重构的节点。尽管CaMKII表达增加对AF病理生理学至关重要，但AF中CaMKII上调的精确分子机制知之甚少。在本期《心血管研究》中，Gao等7为房颤中CaMKII活性增加的潜在新机制提供了令人信服的证据。c-Jun N-末端激酶-2（JNK 2）和CaMK Ⅱ（活性）均随年龄增加而增加，小鼠中组成性JNK 2激活和JNK 2激动剂茴香霉素的应用增加了CaMK Ⅱ d-mRNA和蛋白，而显性负性JNK 2的过表达和特异性JNK 2抑制具有相反的作用。JNK 2介导的CaMKIId-mRNA的增加与转录因子c-jun的磷酸化（激活）（但不激活转录因子2，ATF 2）相关，并导致更强的c-jun与CaMKIId启动子的结合，沿着CaMKIId转录活性的增加，这被JNK 2或c-jun siRNA敲低逆转。这些数据建立JNK 2作为一种新的转录CaMKIId-调节因子，对AF-病理生理学具有潜在的影响。Gao等人的结果7是先前工作的逻辑延伸，表明小鼠中的组成性JNK 2-激活倾向于诱导型AF，可能通过由于CaMKIId上调引起的异常肌浆网（SR）Ca 2 +-泄漏。8尽管CaMKIIId非依赖性效应也可能导致JNK 2致心律失常（例如连接蛋白43），但9只遗传性CaMKIIId抑制的小鼠在用茴香霉素激活JNK 2后未发生起搏诱导的AF，这表明JNK 2可能仅通过CaMKIIId激活诱导AF，至少在小鼠中是如此。除了增加CaMKIId转录外，7体外JNK 2直接磷酸化CaMKIId的经典Thr 287-自磷酸化位点，8尽管仍有待证明这发生在完整的心脏中。这些新发现提出了几个重要问题。JNK 2和CaMKIId之间的关系仅在人类心房中相关; JNK 2是否因果地导致AF患者中较高的CaMKIId活性需要直接证明。cAF患者表现出CaMKIId蛋白水平升高，刺激性Thr 287-自磷酸化水平成比例增加，沿着抑制性Thr 287-自磷酸化水平降低。
Atrial fibrillation (AF) is the most common arrhythmia, which shows a strong increase in prevalence with age and is associated with substantial morbidity and mortality, with worsening heart failure and thromboembolic events being the most prominent complications. Despite the enormous progress in our understanding of the underlying molecular mechanisms promoting AF maintenance and progression, current treatment options with drugs are only moderately effective and have profound side effects including proarrhythmia. Thus, there is a clear unmet need for novel drug options with increased effectivity and improved safety profiles. A better understanding of AF-pathophysiology is expected to foster this development and accumulating evidence has highlighted a central role for abnormal Ca2þ-handling and increased Ca2þ-calmodulindependent protein-kinase II (CaMKII) activity in AF-pathophysiology. 1 CaMKII regulates multiple ion channels, Ca2þ-handling and myofilament proteins and is overexpressed (hyperactive) in patients with persistent (chronic) AF (cAF) 2, 3 as well as in experimental AF. 4–6 CaMKII upregulation promotes atrial arrhythmogenesis through modulation of multiple elements of electrical, Ca2þ-handling and structural remodeling, 1 positioning abnormal CaMKII as a nodal point of AF-promoting atrial remodeling. Despite the critical importance of increased CaMKII expression for AF pathophysiology, the precise molecular mechanisms of upregulated CaMKII in AF are poorly understood. In this issue of Cardiovascular Research, Gao et al. 7 provide compelling evidence for a potential novel mechanism of increased CaMKII activity in AF. They show that in the human atrium phosphorylation (activity) of both c-Jun N-terminal kinase-2 (JNK2) and CaMKII increase in parallel with age and that constitutive JNK2-activation in mice and application of JNK2-agonist anisomycin increase CaMKIId-mRNA and-protein, whereas overexpression of dominant-negative JNK2 and specific JNK2-inhibition have the opposite effect. The JNK2-mediated increase in CaMKIId-mRNA was associated with phosphorylation (activation) of transcription factor c-jun (but not activating transcription-factor-2, ATF2) and resulted in a stronger c-jun binding to CaMKIId promoter along with an increase in transcriptional CaMKIId-activity, which was reversed by either JNK2 or c-jun siRNA knockdown. These data establish JNK2 as a novel transcriptional CaMKIId-regulator with potential implications for AF-pathophysiology.The results of Gao et al. 7 are a logical extension of previous work showing that constitutive JNK2-activation in mice predisposes to inducible AF, likely via abnormal sarcoplasmic reticulum (SR) Ca2þ-leak due to upregulated CaMKIId. 8 Although CaMKIId-independent effects might also contribute JNK2 proarrhythmia (eg on connexin43), 9 mice with genetic CaMKIId-inhibition do not develop pacing-induced AF after JNK2-activation with anisomycin, suggesting that JNK2 might induce AF exclusively via CaMKIId-activation, at least in mice. Besides increasing CaMKIId transcription, 7 in vitro JNK2 directly phosphorylates the classical Thr287-autophosphorylation site of CaMKIId, 8 although it remains to be demonstrated that this occurs in the intact heart. These novel findings raise several important questions. The relationship between JNK2 and CaMKIId is only correlative in human atria; whether JNK2 causally contributes to the higher CaMKIId-activity in AF patients requires direct demonstration. Patients with cAF exhibit enhanced CaMKIId protein levels with a proportional increase in stimulatory Thr287-autophosphorylation, along with reduced inhibitory …