Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure
Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure
复制标题
钙/钙调素依赖性蛋白激酶II导致心房结构重构与心房颤动和心力衰竭相关
DOI：
10.1016/j.hrthm.2019.01.013
复制
发表时间：
2019-07-01
期刊：
影响因子：
5.5
通讯作者：
Donahue, J. Kevin
中科院分区：
文献类型：
--
作者：
Liu, Zhao;Finet, J. Emanuel;Donahue, J. Kevin
背景：房颤（AF）是由可重入机制维持的，部分依赖于心房结构重构。Ca2+/钙调素依赖性蛋白激酶II （CaMKII）活性增加发生在持续性房颤中。普遍的共识是，CaMKII的电生理作用必须是促成因素，但房颤的电重构与CaMKII的电生理作用有很大不同。CaMKII与一些组织的结构重塑有关，但与心房无关。CaMKII在维持房颤中的作用尚不明确。目的探讨CaMKII对房颤相关结构重构的影响。方法利用CaMKII抑制肽CaMKIIn的心房基因转移，在猪af -心力衰竭模型中评估目标。我们使用常规方法，包括体内电生理研究、遥测、western blot、超声心动图和组织学来量化与CaMKII和结构重构相关的节律、功能、微观结构和信号通路。结果在af -心力衰竭早期，CaMKII水平和活性逐渐升高。抑制CaMKII保留心房收缩功能，减轻心房肥厚、纤维化和凋亡，但不影响炎症或肌溶解。这些影响伴随着HDAC4磷酸化的显著降低，p38map -激酶表达的降低，以及JNK亚型磷酸化模式和相对比例的改变。结论：我们的研究结果表明，CaMKII介导心房收缩功能和房颤结构重构相关的信号通路。抑制CaMKII可能是房颤的一种新疗法。这些发现很重要，因为尚未发现心房收缩功能或结构重构的临床相关介质。
BACKGROUND Atrial fibrillation (AF) is sustained by reentrant mechanisms that depend, in part, on atrial structural remodeling. Increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity occurs in persistent AF. A general consensus has been that electrophysiological actions of CaMKII must be the contributing factor, but electrical remodeling in AF differs considerably with electrophysiological effects of CaMKII. CaMKII has been associated with structural remodeling in several tissues, but not the cardiac atria. The role of CaMKII in sustaining AF remains undefined.OBJECTIVE The purpose of this study was to assess the effects of CaMKII on AF-related structural remodeling.METHODS We evaluated the objective in a porcine AF-heart failure model using atrial gene transfer of the CaMKII inhibitory peptide CaMKIIn. We used conventional methods including in vivo electrophysiological study, telemetry, western blot, echocardiography, and histology to quantify rhythm, function, microstructure, and signaling pathways relevant to CaMKII and structural remodeling.RESULTS CaMKII levels and activity increased progressively in the early stages of AF-heart failure. Inhibiting CaMKII preserved atrial contractile function and attenuated atrial hypertrophy, fibrosis, and apoptosis but did not affect inflammation or myolysis. These effects were accompanied by significantly decreased phosphorylation of HDAC4, decreased expression of p38MAP-kinase, and alterations in the phosphorylation pattern and relative ratios of JNK isoforms.CONCLUSION Our findings suggest that CaMKII mediates signaling pathways related to atrial contractile function and structural remodeling in AF. CaMKII inhibition is potentially a novel therapy for AF. These findings are of importance because no clinically relevant mediators of either atrial contractile function or structural remodeling have yet been identified.