H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation
H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation
复制标题
H2S 通过减弱心房颤动期间 Nox4 介导的 ROS 生成来抑制血管紧张素 II 诱导的心房 Kv1.5 上调。
DOI：
10.1016/j.bbrc.2016.12.110
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发表时间：
2017-01-29
影响因子：
3.1
通讯作者：
Gao, Xiuren
中科院分区：
文献类型：
--
作者：
Lu, Guihua;Xu, Chenggui;Gao, Xiuren
我们的前期研究表明，血管紧张素II（Ang II）通过激活ROS依赖的P-Smad 2/3和P-ERK 1/ 2上调Kv1.5的表达，Kv1.5是一个有希望的房颤（AF）治疗靶点。最近的一项研究表明，硫化氢（H2S）可能通过抑制心脏中NADPH氧化酶4（Nox 4）-ROS信号转导来调节血管紧张素II（Ang II）的作用。本研究的目的是确定是否H2S参与调节心房Kv1.5通过ROS相关的机制在AF。培养的新生大鼠心房肌细胞和小猎犬AF模型用于这项研究。在新生大鼠心房肌细胞中，定量PCR和酶免疫分析显示，血管紧张素原，血管紧张素转换酶，和血管紧张素II I型受体（AT 1 R）的mRNA表达水平和血管紧张素II的上清液浓度显着增加过氧化氢（H2 O2）孵育，这些H2 O2诱导的改变被逆转diphenyleneiodonium，夹竹桃素和H2S补充。流式细胞术和Western印迹显示，使用DL炔丙基甘氨酸阻断H2S生物合成增加ROS的产生和Ang II和Kv1.5的表达。硫氢化钠（外源性H2S供体）和Nox 4 siRNA抑制Ang II诱导的ROS产生和Ang II诱导的Kv1.5、P-Smad 2/3、P-ERK 1/2表达。硫氢化钠抑制血管紧张素II诱导的Nox 4上调。在我们的比格犬AF模型中，24 h的快速心房起搏（RAP）增加了心房Ang II浓度，ROS产生以及Nox 4，Kv 1.5，P-Smad 2/3和P-ERK 1/2的蛋白表达。这些RAP诱导的变化被H2S补充和氯沙坦（AT 1 R阻断剂）预处理抑制。总之，我们的研究表明，H2S下调Ang II诱导的心房Kv1.5的表达，通过减弱Nox 4相关的ROS触发的P-Smad 2/3和P-ERK 1/2激活AF。H2S补充将是有益的AF治疗通过抑制心房Kv1.5的表达。(C)2016 Elsevier Inc. All rights reserved.
Our previous study demonstrated that angiotensin II (Ang II) upregulates the expression of Kv1.5, a promising target for atrial fibrillation (AF) therapy, by activating ROS-dependent P-Smad2/3 and P-ERK 1/ 2. A recent study showed that hydrogen sulfide (H2S) may modulate the effects of angiotensin II (Ang II) by inhibiting the NADPH oxidase 4 (Nox4)-ROS signaling in the heart. The present study aimed to determine whether H2S is involved in the regulation of atrial Kv1.5 via ROS-related mechanisms in AF. Cultured neonatal rat atrial myocytes and a beagle model of AF were used for this study. In the neonatal rat atrial myocytes, quantitative PCR and enzyme immunoassays revealed that the mRNA expression levels of angiotensinogen, angiotensin-converting enzyme, and Ang II type I receptor (AT1R) and the Ang II supernatant concentration were significantly increased by hydrogen peroxide (H2O2) incubation, and these H2O2-induced alterations were reversed by diphenyleneiodonium, apocynin and H2S supplementation. Flow cytometry and Western blotting revealed that blockade of H2S biosynthesis using DLpropargylglycine increased ROS production and the expression of Ang II and Kv1.5. Sodium hydrosulfide (an exogenous H2S donor) and Nox4 siRNA inhibited Ang II-induced ROS production and Ang II-induced expression of Kv1.5, P-Smad2/3, P-ERK 1/2. Sodium hydrosulfide suppressed the Ang II-induced upregulation of Nox4. In our beagle AF model, 24 h of rapid atrial pacing (RAP) increased the atrial Ang II concentration, ROS production and the protein expression of Nox4, Kv1.5, P-Smad2/3 and P-ERK 1/2. These RAP-induced changes were inhibited by H2S supplementation and losartan (an AT1R blocker) pretreatment. In conclusion, our study indicates that H2S downregulates Ang II-induced atrial Kv1.5 expression by attenuating Nox4-related ROS-triggered P-Smad2/3 and P-ERK 1/2 activation during AF. H2S supplementation would be beneficial for AF treatment via the suppression of atrial Kv1.5 expression. (C) 2016 Elsevier Inc. All rights reserved.