AMPK upregulates KCa2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

• Published in: Biochemical pharmacology Vol. 183; p. 114337
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-01-2021
• Subjects: Adenosine monophosphate-activated protein kinase; Endothelial cells; Mesenteric resistance arteries; Small-conductance Ca2+-activated potassium channels; MEF2; eNOS; Adenosine monophosphate-activated protein kinase; EDH; Mesenteric resistance arteries; Endothelial cells; Small-conductance Ca2+-activated potassium channels; KCa3.1; KCa2.3; ERK5; AMPK; KLF2/4; HUVECs
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2020.114337

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The opening of endothelial small-conductance calcium-activated potassium channels (KCa2.3) 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 KCa2.3-mediated EDH-type vasodilation. Using bioinformatics analysis and myograph system, we investigated the regulation by AMPK of KCa2.3 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 KCa2.3 expression. Such effects were abolished by AMPK inhibitor (compound C) or AMPK α1-/α2-siRNA, extracellular-signal-regulated-kinase 5 (ERK5) inhibitor (ERK5-IN-1), and specific siRNA to myocyte-enhancer factor 2 (MEF2) or krüppel-like factor 2/4 (KLF2/4). KCa2.3 expression was significantly reduced in mesenteric resistance arteries in AMPKα2 knockout mice when compared with littermate control mice. Furthermore, in high-fat diet fed mice, 2-week treatment with AICAR restored endothelial KCa2.3 expression in mesenteric resistance arteries with improved endothelial dysfunction. Our results demonstrate that activation of AMPK upregulates KCa2.3 channel expression through the ERK5–MEF2–KLF2/4 signaling pathway in vascular endothelium, which contributes to benefits through KCa2.3-mediated EDH-type vasodilation in mesenteric resistance arteries.