SNX17 produces anti-arrhythmic effects by preserving functional SERCA2a protein in myocardial infarction
SNX17 produces anti-arrhythmic effects by preserving functional SERCA2a protein in myocardial infarction
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SNX17 通过在心肌梗塞中保留功能性 SERCA2a 蛋白产生抗心律失常作用
DOI：
10.1016/j.ijcard.2018.07.025
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发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
Shan, Hongli
中科院分区：
文献类型：
--
作者：
Zhao, Dandan;Li, Xuelian;Shan, Hongli
背景资料：分选连接蛋白17（SNX 17）是一种重要的细胞质衔接蛋白，其调节膜蛋白的内体运输以确定其再循环和/或降解。SNX 17在心血管病理生理学中的潜在作用尚未报道。方法和结果：心律失常监测使用标准肢体导联II心电图仪，并通过超声心动图确定心脏性能在心肌梗死（MI）的大鼠模型左前降支冠状动脉结扎。我们发现SNX 17在缺血心肌中显著下调。由于SNX 17替代减轻了MI心脏的有害改变，因此下调导致心脏电紊乱和收缩功能障碍。具体而言，使用RNA干扰沉默SNX 17表达引起细胞内Ca 2+过载，如静息[Ca-2（+）]（i）的异常升高和Ca 2+衰减的减速所揭示的，而使用载体SNX 17过表达引起相反的效果。此外，沉默SNX 17后，SERCA 2a的蛋白水平显着降低。免疫组化结果显示SNX 17与SERCA 2a共定位，免疫共沉淀结果显示SNX 17的phox同源结构域与SERCA 2a蛋白结合。结论：SNX 17的异常下调参与了缺血性心脏电生理和收缩功能的损害。SNX 17是一种内源性抗心肌缺血因子，通过保留MI中的功能性SERCA 2a蛋白发挥作用，从而为MI的管理提供了一种新的策略，以减轻缺血性心肌损伤。(C)2018爱思唯尔B. V.保留所有权利。
Background: Sorting nexin 17 (SNX17) is a critical cytoplasmic adaptor protein that regulates endosomal trafficking of membrane proteins to determine their recycling and/or degradation. The potential role of SNX17 in cardiovascular pathophysiology has not been reported.Methods and results: Cardiac arrhythmias were monitored using standard limb lead II electrocardiograph, and cardiac performances were determined by echocardiography in a rat model of myocardial infarction (MI) created by left anterior descending coronary artery ligation. We found that SNX17 was substantially downregulated in ischemic myocardium. The downregulation contributed to the cardiac electrical disturbances and contractile dysfunction as SNX17 replacement mitigated the detrimental alterations of MI hearts. Specifically, silence of SNX17 expression using RNA interference caused intracellular Ca2+ overload as revealed by the abnormal rise of resting [Ca-2(+)](i) and deceleration of Ca2+ decay, whereas SNX17 overexpression using vectors elicited the opposite effects. Moreover, the protein level of SERCA2a was significantly decreased by silencing SNX17. Immuno-histochemishy indicated that SNX17 and SERCA2a were co-localized, and co-immunoprecipitation revealed the binding between the phox-homology domain of SNX17 and SERCA2a protein. Furthermore, lysosome inhibitor chloroquine prevented SNX17 silencing-induced reduction of SERCA2a protein level.Conclusion: Abnormal downregulation of SNX17 contributes to ischemic damages of cardiac electrophysiology and contractile function. SNX17 is an endogenous anti-arrhythmic factor acting by preserving functional SERCA2a protein in MI thereby offering a new strategy for the management of MI to alleviate ischemic myocardial injuries. (C) 2018 Elsevier B.V. All rights reserved.