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AMPKα2 Deletion Causes Aberrant Expression and Activation of NAD(P)H Oxidase and Consequent Endothelial Dysfunction In Vivo: Role of 26S Proteasomes
Open accessAbstract
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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“Additional evidence supporting AMPK protection against oxidative stress is that AMPK negatively regulates NOX by reducing its phosphorylation and preventing P47phox’s translocation to membrane [70,151].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [70]
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2 retracted
Xu, J., Wu, Y., Song, P., Zhang, M., Wang, S., & Zou, M. (2007) · Circulation · doi:10.1161/circulationaha.106.684795 · Cited by 193
RetractedWang, S., Xu, J. C., Song, P., Viollet, B., & Zou, M. (2009) · Diabetes · doi:10.2337/db09-0267 · Cited by 137
RetractedPhosphorylation meets ubiquitination: the control of NF-κB activity
Karin, M., & Ben-Neriah, Y. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.621 · Cited by 4,766
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NADPH Oxidases, Reactive Oxygen Species, and Hypertension
Paravicini, T. M., & Touyz, R. M. (2008) · Diabetes Care · doi:10.2337/dc08-s247 · Cited by 738
Zang, M., Xu, S., Maitland, K. A., Zuccollo, A., Hou, X., Jiang, B., Wierzbicki, M., Verbeuren, T. J., & Cohen, R. A. (2006) · Diabetes · doi:10.2337/db05-1188 · Cited by 672
NADPH Oxidases: Functions and Pathologies in the Vasculature
Lassègue, B., & Griendling, K. K. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.181610 · Cited by 592
Direct Evidence of Endothelial Oxidative Stress With Aging in Humans
Donato, A. J., Eskurza, I., Silver, A., Levy, A., Pierce, G. L., Gates, P. E., & Seals, D. R. (2007) · Circulation Research · doi:10.1161/01.res.0000269183.13937.e8 · Cited by 566
Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Taguchi, T., Matsumura, T., & Araki, E. (2006) · Diabetes · doi:10.2337/diabetes.55.01.06.db05-0943 · Cited by 504
Hattori, Y., Suzuki, K., Hattori, S., & Kasai, K. (2006) · Hypertension · doi:10.1161/01.hyp.0000221429.94591.72 · Cited by 487
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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.
- Venue
- Circulation Research
- Published
- 2010-04-02
- Volume
- 106
- Issue
- 6
- Pages
- 1117-1128
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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