AMPK upregulates K(Ca)2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

Pang Zheng-Da; Wang Yan; Song Zheng; She Gang; Ma Xiao-Zhen; Sun Xia; Wu Wei; Lai Bao-Chang; Zhang Jiao; Zhang Yi; Du Xiao-Jun; Shyy John Y. J.; Deng Xiu-Ling

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AMPK upregulates K(Ca)2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

机译：AMPK上调k（CA）2.3频道和改善饮食诱导的肥胖小鼠内皮功能障碍

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The opening of endothelial small-conductance calcium-activated potassium channels (K(Ca)2.3) is essential for endothelium-dependent hyperpolarization (EDH), which predominantly occurs in small resistance arteries. Adenosine monophosphate-activated protein kinase (AMPK), an important metabolic regulator, has been implicated in regulating endothelial nitric oxide synthase activity. However, it was unclear whether AMPK regulated endothelial K(Ca)2.3-mediated EDH-type vasodilation. Using bioinformatics analysis and myograph system, we investigated the regulation by AMPK of K(Ca)2.3 in human umbilical vein endothelial cells (HUVECs) or mouse second-order mesenteric resistance arteries. In HUVECs, AMPK activation either by activators (AICAR, A769662 and MK-8722) or expression of the constitutively active form of AMPK significantly upregulated K(Ca)2.3 expression. Such effects were abolished by AMPK inhibitor (compound C) or AMPK alpha 1-/alpha 2-siRNA, extracellular-signal-regulated-kinase 5 (ERK5) inhibitor (ERK5-IN-1), and specific siRNA to myocyte-enhancer factor 2 (MEF2) or kruppel-like factor 2/4 (KLF2/4). K(Ca)2.3 expression was significantly reduced in mesenteric resistance arteries in AMPK alpha 2 knockout mice when compared with littermate control mice. Furthermore, in high-fat diet fed mice, 2-week treatment with AICAR restored endothelial K(Ca)2.3 expression in mesenteric resistance arteries with improved endothelial dysfunction. Our results demonstrate that activation of AMPK upregulates K(Ca)2.3 channel expression through the ERK5-MEF2-KLF2/4 signaling pathway in vascular endothelium, which contributes to benefits through K(Ca)2.3-mediated EDH-type vasodilation in mesenteric resistance arteries.

机译：内皮小导电钙活化钾通道（K（CA）2.3）的开口对于内皮依赖性超极化（EDH）至关重要，这主要发生在小型抵抗动脉中。腺苷均磷酸酯活化蛋白激酶（AMPK）是一种重要的代谢调节剂，已经涉及调节内皮一氧化氮合酶活性。然而，目前尚不清楚AMPK调节内皮K（CA）2.3介导的EDH型血管舒张。使用生物信息学分析和象形文学系统，我们调查了K（CA）2.3在人脐静脉内皮细胞（HUVECS）或小鼠二阶肠系膜抗性动脉中的调节。在Huvecs，AMPK活化剂通过激活剂（AICAR，A769662和MK-8722）或组成型活性形式的AMPK的表达显着上调K（CA）2.3表达。通过AMPK抑制剂（化合物C）或AMPKα1-/α-2- siRNA，细胞外 - 信号调节 - 激酶5（ERK5）抑制剂（ERK5-IN-1）和特异性siRNA对肌细胞增强剂因子进行这种影响2（MEF2）或KRUPPEL样因子2/4（KLF2 / 4）。与枯结窝对照小鼠相比，在AMPKα2敲除小鼠中，在肠系膜抗性动脉中显着降低了K（CA）2.3表达。此外，在高脂饮食喂养小鼠中，用AICAR恢复的内皮K（CA）2.3在肠系膜抗性动脉中的表达，具有改进的内皮功能障碍。我们的结果表明，通过在血管内皮中的ERK5-MEF2-KLF2 / 4信号通路上，AMPK的激活通过ERK5-MEF2-KLF2 / 4信号通路，这有助于通过K（CA）2.3介导的肠系膜抗性动脉中的edh型血管舒张益处。

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来源
《Biochemical Pharmacology》 |2021年第1期|共14页
作者
Pang Zheng-Da; Wang Yan; Song Zheng; She Gang; Ma Xiao-Zhen; Sun Xia; Wu Wei; Lai Bao-Chang; Zhang Jiao; Zhang Yi; Du Xiao-Jun; Shyy John Y. J.; Deng Xiu-Ling;
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作者单位

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Univ Calif San Diego Div Cardiol Dept Med 9500 Gilman Dr La Jolla CA 92093 USA;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

Univ Calif San Diego Div Cardiol Dept Med 9500 Gilman Dr La Jolla CA 92093 USA;

Xi An Jiao Tong Univ Sch Basic Med Sci Cardiovasc Res Ctr Dept Physiol &

Pathophysiol Hlth Sci;

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原文格式 PDF
正文语种 eng
中图分类药理学;
关键词
Mesenteric resistance arteries; Endothelial cells; Small-conductance Ca2+-activated potassium channels; Adenosine monophosphate-activated protein; kinase;

机译：肠系膜抵抗动脉;内皮细胞;小电导Ca2 + - 活化的钾通道;腺苷一磷酸活性蛋白;激酶;

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AMPK upregulates K(Ca)2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

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