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Cited by 296Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressNeutrophil, Myeloperoxidase and Oxidative Mechanisms

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.

AMPKα2 Deletion Causes Aberrant Expression and Activation of NAD(P)H Oxidase and Consequent Endothelial Dysfunction In Vivo: Role of 26S Proteasomes

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Wang, Shuangxi, Zhang, Miao, Liang, Bin, Xu, Jian, Xie, Zhonglin, Liu, Chao, Viollet, Benoit, Yan, Daoguang, Zou, Ming-Hui·2010·Circulation Research
DOI 10.1161/circresaha.109.212530PMC PMC2920052
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Abstract

RATIONALE: AMP-activated protein kinase (AMPK) is an energy sensor and ubiquitously expressed in vascular cells. Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established. OBJECTIVE: The aim of this study is to examine the effects of AMPK in regulating NAD(P)H oxidase, oxidative stress, and endothelial function. METHODS AND RESULTS: The markers of oxidative stress, NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 to -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of nuclear factor (NF)-kappaB (p50 and p65) were examined in cultured human umbilical vein endothelial cells and mouse aortas isolated from AMPKalpha2 deficient mice. Compared to the wild type, acetylcholine-induced endothelium-dependent relaxation was significantly impaired in parallel with increased production of oxidants in AMPKalpha2(-/-) mice. Further, pretreatment of aorta with either superoxide dismutase (SOD) or tempol or apocynin significantly improved acetylcholine-induced endothelium-dependent relaxation in AMPKalpha2(-/-) mice. Analysis of aortic endothelial cells from AMPKalpha2(-/-) mice and human umbilical vein endothelial cells expressing dominant negative AMPK or AMPKalpha2-specific siRNA revealed that loss of AMPK activity increased NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 and -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of NF-kappaB (p50 and p65), whereas AMPK activation by AICAR or overexpression of constitutively active AMPK had the opposite effect. Consistently, we found that genetic deletion of AMPKalpha2 in low-density lipoprotein receptor knockout (LDLr(-/-)) strain markedly increased 26S proteasome activity, IkappaB degradation, NF-kappaB transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, and endothelial dysfunction, all of which were largely suppressed by chronic administration of MG132, a potent cell permeable proteasome inhibitor. CONCLUSIONS: We conclude that AMPKalpha2 functions as a physiological suppressor of NAD(P)H oxidase and ROS production in endothelial cells. In this way, AMPK maintains the nonatherogenic and noninflammatory phenotype of endothelial cells.

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Metadata

Authors
Wang, S., Zhang, M., Liang, B., Xu, J., Xie, Z., Liu, C., Viollet, B., Yan, D., & Zou, M.-H.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • From the Section of Endocrinology and Diabetes (S.W., M.Z., B.L., J.X., Z.X., C.L., D.Y., M.-H.Z.), Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City; Institut Cochin (B.V.), Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), University Paris Descartes, Paris, France; Institut National de la Santé et de la Recherche Médicale (B.V.), U1016, Paris, France; and College of Life Science (B.V.), Jinan University, Guangzhou, China.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-04-02
Volume
106
Issue
6
Pages
1117-1128
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.109.212530
PMC
PMC2920052
OpenAlex
W1964266642
Cited by
296
References
41
Citations by year
2026: 4 · 2025: 3 · 2024: 9 · 2023: 12 · 2022: 8 · 2021: 13 · 2020: 24 · 2019: 18 · 2018: 26 · 2017: 28 · 2016: 34 · 2015: 27 · 2014: 26 · 2013: 20 · 2012: 20
FWCI
13.63
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL105157, HL 079584, R01HL079584, HL-080499, HL096032, HL074399, R01HL074399, R01HL080499, HL-089920, R01HL110488, R01HL089920, R01HL096032)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
AMPKα2, AMPK, NADPH oxidase, endothelial dysfunction, oxidative stress, NF-κB signaling, 26S proteasome, superoxide production, NOX1, NOX4, LDL receptor, atherosclerosis, acetylcholine-induced relaxation, AICAR, tempol, apocynin, superoxide dismutase, p47phox, p67phox, gp91phox, LDL oxidation
MeSH terms
NF-KappaB Inhibitor alpha, Acetophenones, Acetylcholine, Aminoimidazole Carboxamide, Animals, Antioxidants, Cells, Cultured, Cyclic N-Oxides, Dose-Response Relationship, Drug, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Humans, Interferon-gamma, Interleukin-2, Isoenzymes, Leupeptins, Male, Mice, Inbred C57BL, Nitroprusside, Receptors, LDL, Ribonucleotides, Spin Labels, Superoxides, Superoxide Dismutase, Transfection, Vasodilation, Vasodilator Agents, Gene Expression Regulation, Enzymologic, NF-kappa B, Gene Deletion, Mice, Knockout, Oxidative Stress, Inflammation Mediators, NADPH Oxidases, I-kappa B Proteins, RNA Interference, Endothelial Cells, Proteasome Endopeptidase Complex, Mice, AMP-Activated Protein Kinases, Proteasome Inhibitors

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