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

• Published in: Biochemical pharmacology 2021-01, 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: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - biosynthesis; Animals; Diet, High-Fat - adverse effects; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Indoles - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity - etiology; Obesity - metabolism; Oximes - pharmacology; RNA, Small Interfering - pharmacology; Small-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Small-Conductance Calcium-Activated Potassium Channels - biosynthesis; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 1873-2968

The opening of endothelial small-conductance calcium-activated potassium channels (K 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 2.3-mediated EDH-type vasodilation. Using bioinformatics analysis and myograph system, we investigated the regulation by AMPK of K 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 2.3 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). K 2.3 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 K 2.3 expression in mesenteric resistance arteries with improved endothelial dysfunction. Our results demonstrate that activation of AMPK upregulates K 2.3 channel expression through the ERK5-MEF2-KLF2/4 signaling pathway in vascular endothelium, which contributes to benefits through K 2.3-mediated EDH-type vasodilation in mesenteric resistance arteries.