Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.
Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.
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DOI：
10.1371/journal.pone.0138711
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mathias RT
中科院分区：
文献类型：
--
作者：
Kim J;Gao J;Cohen IS;Mathias RT
我们最近描述了犬心脏中的自分泌肾素血管紧张素系统（RAS）。血管紧张素II型1受体（AT1Rs）的激活诱导电重构，包括瞬时外向钾电流Ito的抑制，动作电位（AP）的延长，钙进入增加和收缩性增加。小鼠心脏的电特性与狗心脏的电特性有很大的不同，但如果在小鼠中存在类似的系统，则可以通过基因操作进行独特的研究。为了研究RAS在小鼠中的存在，我们在分离的肌细胞中测量了APs和Ito。应用血管紧张素II (A2) 2小时或更长时间可降低Ito幅度，而不影响电压依赖性，并以剂量依赖性方式延长APs。从剂量抑制曲线来看，Ito的快、慢组分（Ito，fast和IK，slow）似乎受到[A2]的一致调控，在A2浓度约为400 nM时，抑制率为50%。这种非常高的K0.5与全身A2效应不一致，但与小鼠心脏的自分泌RAS一致。预施用微管不稳定剂秋水仙碱消除了A2对Ito和AP持续时间的影响，表明这些影响取决于细胞内运输。应用偏向性激动剂SII （[Sar1-Ile4-Ile8]A2）刺激受体内化而不激活G蛋白，导致Ito减少和AP延长，类似于A2诱导的变化。这些数据证明了AT1R介导的Ito在小鼠心脏中的调节作用。此外，所有测量到的特性都与狗的心脏相似，这表明自分泌RAS可能是跨物种存在的基本反馈系统。
We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.