Cited by 264Nitric Oxide and Endothelin EffectsMetabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase Signaling

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AMP-Activated Protein Kinase Functionally Phosphorylates Endothelial Nitric Oxide Synthase Ser633

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Chen, Zhen, Peng, I-Chen, Sun, Wei, Su, Mei-I, Hsu, Pang-Hung, Fu, Yi, Zhu, Yi, DeFea, Kathryn, Pan, Songqin, Tsai, Ming-Daw, Shyy, John Y-J.·2009·Circulation Research

DOI 10.1161/circresaha.108.187567PMC PMC2761102

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Abstract

Endothelial nitric oxide synthase (eNOS) plays a central role in maintaining cardiovascular homeostasis by controlling NO bioavailability. The activity of eNOS in vascular endothelial cells (ECs) largely depends on posttranslational modifications, including phosphorylation. Because the activity of AMP-activated protein kinase (AMPK) in ECs can be increased by multiple cardiovascular events, we studied the phosphorylation of eNOS Ser633 by AMPK and examined its functional relevance in the mouse models. Shear stress, atorvastatin, and adiponectin all increased AMPK Thr172 and eNOS Ser633 phosphorylations, which were abolished if AMPK was pharmacologically inhibited or genetically ablated. The constitutively active form of AMPK or an AMPK agonist caused a sustained Ser633 phosphorylation. Expression of gain-/loss-of-function eNOS mutants revealed that Ser633 phosphorylation is important for NO production. The aorta of AMPKalpha2(-/-) mice showed attenuated atorvastatin-induced eNOS phosphorylation. Nano-liquid chromatography/tandem mass spectrometry (LC/MS/MS) confirmed that eNOS Ser633 was able to compete with Ser1177 or acetyl-coenzyme A carboxylase Ser79 for AMPKalpha phosphorylation. Nano-LC/MS/MS confirmed that eNOS purified from AICAR-treated ECs was phosphorylated at both Ser633 and Ser1177. Our results indicate that AMPK phosphorylation of eNOS Ser633 is a functional signaling event for NO bioavailability in ECs.

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10.1161/res.88.8.756 · DOI
10.1161/res.88.11.e68 · DOI
10.1042/bj3510095 · DOI

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Authors: Chen, Z., Peng, I.-C., Sun, W., Su, M.-I., Hsu, P.-H., Fu, Y., Zhu, Y., DeFea, K., Pan, S., Tsai, M.-D., & Shyy, J. Y.-J.
Affiliations: University of California, Riverside (US)
ORCID: Chen, Zhen
Peng, I-Chen
Sun, Wei
Hsu, Pang-Hung
Zhu, Yi
DeFea, Kathryn
Tsai, Ming-Daw
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2009-02-27
Volume: 104
Issue: 4
Pages: 496-505
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/circresaha.108.187567
PMC: PMC2761102
OpenAlex: W1966733021
Cited by: 264
References: 46
Citations by year: 2026: 8 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 10 · 2021: 17 · 2020: 19 · 2019: 12 · 2018: 13 · 2017: 13 · 2016: 14 · 2015: 22 · 2014: 27 · 2013: 15 · 2012: 26
FWCI: 16.35
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (HL-77448, R01HL089940, R01HL077448, HL89940)
National Institute of General Medical Sciences (R01GM066151)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: AMPK, endothelial nitric oxide synthase, eNOS Ser1177 phosphorylation, nitric oxide bioavailability, shear stress, atorvastatin, adiponectin, AMPKα2, vascular endothelial cells, post-translational modification, AICAR
MeSH terms: Atorvastatin, Acetyl-CoA Carboxylase, Aminoimidazole Carboxamide, Animals, Cattle, Cells, Cultured, Chromatography, Liquid, Enzyme Activation, Heptanoic Acids, Humans, Mice, Inbred C57BL, Mutation, Nitric Oxide, Phosphorylation, Protein Processing, Post-Translational, Pyrazoles, Pyrimidines, Pyrroles, Ribonucleotides, Serine, Stress, Mechanical, Time Factors, Transfection, Signal Transduction, Mice, Knockout, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA Interference, RNA, Small Interfering, Nanotechnology, Endothelial Cells, Protein Kinase Inhibitors, Mice, Adiponectin, Nitric Oxide Synthase Type III, Tandem Mass Spectrometry, AMP-Activated Protein Kinases

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AMP-Activated Protein Kinase Functionally Phosphorylates Endothelial Nitric Oxide Synthase Ser633

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