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AMP-Activated Protein Kinase Functionally Phosphorylates Endothelial Nitric Oxide Synthase Ser633
Open accessAbstract
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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“Increasing evidence suggests that AMPK is essential in maintaining NO bioavailability.”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [163]
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“AMPK is activated and in turn acts as a direct activator of eNOS by phosphorylating its Ser1177 residue [163].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [163]
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Hallows, K. R., Mount, P. F., Pastor‐Soler, N. M., & Power, D. A. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00005.2010 · Cited by 158
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AMPK and NRF2: Interactive players in the same team for cellular homeostasis?
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“Furthermore, Spermine NONOate, an exogenous source of NO, reversed LG-induced mitochondrial hyperpolarization (P=0.97 vs. NG alone, P=0.007 vs. LG alone), while L-NAME significantly increased mitochondrial membrane potential in the setting of NG (P=0.004 vs. NG alone).”
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“…AMPK is the only kinase identified to date that can potentially phosphorylate eNOS on more than one site, that is, on Ser1177 (29) and Ser633 (28), both activating sites in the reductase domain of the enzyme, leading to eNOS activation in endothelial cells and mouse aorta (169), although…”
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“Chen et al have found low levels of Ator-induced eNOS phosphorylation in the aortas of AMPKa2 mice [34], suggesting that AMPKa is a primary kinase that phosphorylates eNOS.”
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“It has been suggested that the activation of AMPK is, in part, regulated by endogenous NO in a positive feedback mechanism, such that an increase in NO activates AMPK, which further augments NOS activity and NO production (8, 29, 50).”
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“H2O2-activated AMPK phosphorylates eNOS on serine 1177, but does not phosphorylate nNOS in cardiac myocytes (Sartoretto et al., 2011) and phosphorylates eNOS on serine 633 in vascular endothelial cells (Chen et al., 2009).”
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“Nitrite and nitrate can activate this important regulator of cellular energy homeostasis,(196,197) which in turn may activate eNOS by stimulating enzyme phosphorylation.(198) As AMPK is deeply involved in regulating glucose metabolism and cellular energetics, its activation by nitrate and nitrite may also explain the…”
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Sartoretto, J. L., Kalwa, H., Pluth, M. D., Lippard, S. J., & Michel, T. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111331108 · Cited by 86
“11), including the AMP-activated protein kinase (AMPK), which phosphorylates the enzyme on serine 1177 in cardiac myocytes (12) and on serine 633 in vascular endothelial cells (13).”
BackgroundFish oil and vascular endothelial protection: Bench to bedside
Balakumar, P., & Taneja, G. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.05.005 · Cited by 81
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“In the vasculature, activation of endothelial AMPK has been shown to phosphorylate eNOS at Ser1177 and Ser633, stimulating NO release (Chen et al., 2009; Mariman and Wang, 2010) and subsequent vasodilatation of both large conduit and resistance blood vessels (Wang et al., 2009b; Bradley et al.,…”
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“…kinase (AMPK) and ERK, and phosphatases such as protein phosphatase (PP)1 and PP2A in response to multiple stimuli via shear stress, growth factors, insulin, etc. (Dimmeler et al., 1999; Michell et al., 1999; 2001; Fleming et al., 2001; Mount et al., 2007; Chen et al., 2009; Xiao et al., 2011).”
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“Since AMPK phosphorylates eNOS at both Ser-633 and Ser-1177 to enhance the eNOS-derived NO bioavailability (5), we then studied whether CGRP can increase the eNOS phosphorylation, and if so, whether this activation is mediated through AMPK.”
BackgroundImmunometabolism of AMPK in insulin resistance and atherosclerosis
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“In endothelial cells simvastatin induces eNOS Ser633 phosphorylation in an AMP-activated protein kinase (AMPK)-mediated way (37).”
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Adipokines and the cardiovascular system: mechanisms mediating health and disease
Northcott, J. M., Yeganeh, A., Taylor, C. G., Zahradka, P. C., & Wigle, J. T. (2012) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y2012-053 · Cited by 72
Ford, R. J., Teschke, S. R., Reid, E. B., Durham, K. K., Kroetsch, J. T., & Rush, J. W. E. (2012) · Journal of Hypertension · doi:10.1097/hjh.0b013e32835050ca · Cited by 70
“Mechanisms suggested in other work that could account for enhanced nitric oxide bioavailability or bioactivity with AMPK activation include phosphorylation of eNOS activation site Ser633 [14], formation of active eNOS complexes [12,15], increased sensitivity of downstream signaling mechanisms, or other yet unidentifie…”
BackgroundEnkhjargal, B., Godo, S., Sawada, A., Nergui, S., Saito, H., Noda, K., Satoh, K., & Shimokawa, H. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.303735 · Cited by 70
“As a metabolic sensor, eAMPK plays an important role in metabolic regulation of blood flow,(24,26) which is also regulated by endothelial NO synthase (eNOS)(27,28) through AMPK activation.(29,30) However, the role of eAMPK in EDH remains to be elucidated.”
BackgroundRossoni, L. V., Wareing, M., Wenceslau, C. F., Al‐Abri, M., Cobb, C., & Austin, C. E. (2011) · Clinical Science · doi:10.1042/cs20110259 · Cited by 69
Li, X.-D., Yang, Y.-J., Geng, Y., Chen, J., Hu, F., Zhao, J.-L., Zhang, H.-T., Cheng, Y.-T., Qian, H., Wang, L., et al. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00459.2010 · Cited by 69
“Previous studies have found that the phosphorylation of Ser 1179, regulated by the PKA and PI3K/Akt pathways, is pivotal for eNOS activation in response to shear stress, adiponectin, and statins (6, 10, 11), whereas the phosphorylation of Ser, mainly activated by PKA and AMPK (2, 4, 7), is the most potent in stimulati…”
BackgroundInfluentialJansen, T., Kvandová, M., Daiber, A., Stamm, P., Frenis, K., Schulz, E., Münzel, T., & Kröller-Schön, S. (2020) · Antioxidants · doi:10.3390/antiox9060525 · Cited by 68
“Endothelium-derived NO is the key player in the regulation of the vascular tone [74,75].”
BackgroundRodríguez, C., Contreras, C., Medina, J. S., Muñoz, M., Corbacho, C., Carballido, J., García‐Sacristán, A., Hernández, M., López, M., Rivera, L., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101575 · Cited by 70
“response to physiological stimuli such as shear stress [7,11,12] or adipokines acting via Gq receptors like adiponectin and leptin [1].”
BackgroundPsefteli, P., Kitscha, P., Vizcay‐Barrena, G., Fleck, R. A., Chapple, S. J., Mann, G. E., Fowler, M. I., & Siow, R. C. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101816 · Cited by 67
“6A and B) which are critical for NO output [52, 53].”
BackgroundProtective effects of AMP‐activated protein kinase in the cardiovascular system
Xu, Q., & Si, L. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01179.x · Cited by 68
“Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd Ser633, was identified; the authors confirmed that AMPK phosphorylation of eNOS Ser633 is a functional signalling event contributing to nitric oxide bioavailability in endothelial cells [71].”
BackgroundPPARδ Activation Protects Endothelial Function in Diabetic Mice
Tian, X. Y., Wong, W. T., Wang, N., Lu, Y., Cheang, W. S., Liu, J., Liu, L., Liu, Y., Lee, S. S. T., Chen, Z., et al. (2012) · Diabetes · doi:10.2337/db12-0117 · Cited by 67
“negative Akt (Ad-DN-Akt) was described previously (33).”
Mackenzie, R. M., Salt, I. P., Miller, W. H., Logan, A., Ibrahim, H., Degasperi, A., Dymott, J. A., Hamilton, C. A., Murphy, M. P., Delles, C., et al. (2012) · Clinical Science · doi:10.1042/cs20120239 · Cited by 67
The role of endothelial mechanosensitive genes in atherosclerosis and omics approaches
Simmons, R. D., Kumar, S., & Jo, H. (2015) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2015.11.005 · Cited by 71
Cardiovascular impact of drugs used in the treatment of diabetes
Triggle, C. R., & Ding, H. (2014) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622314546125 · Cited by 67
“Activation of AMPK might also be a contributing factor to the beneficial effects of metformin on the endothelium as AMPK also phosphorylates and activates eNOS [Chen et al. 2009].”
BackgroundCui, X., Liu, X., Feng, H., Zhao, S., & Gao, H. (2012) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b12-00598 · Cited by 69
Siragusa, M., Justo, A. F. O., Malacarne, P. F., Strano, A., Buch, A., Withers, B., Peters, K. G., & Fleming, I. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa213 · Cited by 67
Tissue-specific role and associated downstream signaling pathways of adiponectin
Roy, B., & Palaniyandi, S. S. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00587-4 · Cited by 65
“Chen Z, et al. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633.”
BackgroundChatauret, N. P., Coudroy, R., Delpech, P., Vandebrouck, C., Hosni, S., Scépi, M., & Hauet, T. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12904 · Cited by 64
Sowers, J. R., Habibi, J., Aroor, A. R., Yang, Y., Lastra, G., Hill, M. A., Whaley‐Connell, A. T., Jaisser, F., & Jia, G. (2019) · Metabolism · doi:10.1016/j.metabol.2019.153946 · Cited by 63
“Indeed, AMPKα activation is necessary for phosphorylation and optimal activation of eNOS [16], and Sirt1 promotes phosphorylation/activation of eNOS through deacetylating lysine 496 and 506 [17].”
BackgroundHwang, Y. P., Kim, H. G., Hiền, T. T., Jeong, M. H., Jeong, T. C., & Jeong, H. G. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2011.08.017 · Cited by 64
Back to the heart: The protective role of adiponectin
Caselli, C., D’Amico, A., Cabiati, M., Prescimone, T., Ry, S. D., & Giannessi, D. (2014) · Pharmacological Research · doi:10.1016/j.phrs.2014.03.003 · Cited by 61
Ducsay, C. A., & Myers, D. A. (2011) · Journal of Endocrinology · doi:10.1530/joe-11-0034 · Cited by 58
“Recently, Chen et al. (2009) showed that AMPK phosphorylates eNOS at Ser633 and is a functional signal of NO bioavailability.”
BackgroundTargeting the NO/superoxide ratio in adipose tissue: relevance to obesity and diabetes management
Janković, A., Korać, A., Buzadžić, B., Stančić, A., Otašević, V., Ferdinándy, P., Daiber, A., & Korać, B. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13498 · Cited by 60
“In endothelial cells, AMPK activates eNOS via phosphorylation at Ser1177 and Ser633 (Chen et al., 1999, 2009).”
BackgroundWang, X., Song, S., Xiao, H., Gao, P., Li, X.-J., & Si, L. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000363031 · Cited by 58
VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1
Spengler, K., Kryeziu, N., Größe, S., Mosig, A. S., & Heller, R. (2020) · Cells · doi:10.3390/cells9030687 · Cited by 60
Teng, R., Du, J., Afolayan, A. J., Eis, A., Shi, Y., & Konduri, G. G. (2012) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00200.2012 · Cited by 54
“Increased ROS formation has been shown to activate AMPK (52, 53) in some vascular beds, which may increase the activity of eNOS (5, 6) and antioxidant 0 2 4 6 8 10 12 14”
BackgroundChing, L., Chen, C., Su, K., Hou, H., Shyue, S., Kou, Y. R., & Lee, T. (2012) · Molecular Medicine · doi:10.2119/molmed.2011.00461 · Cited by 54
“These findings are in line with previous findings that AMPK functionally phosphorylates eNOS at Ser635 and Ser1179 in ECs and subsequently promotes NO bioavailability in ECs (27,28).”
BackgroundResultFord, R. J., & Rush, J. W. E. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00597.2010 · Cited by 53
“A number of cell culture and in vitro biochemical experiments have demonstrated that AMPK can phosphorylate eNOS at activation site Ser(1177) (5, 6, 8, 12, 29, 40) and that AMPK activation has been associated with increased NO release from endothelial cells (5, 8, 12, 40), establishing NO as a potential mediator of en…”
BackgroundInfluentialEffects of exercise training and resveratrol on vascular health in aging
Gliemann, L., Nyberg, M., & Hellsten, Y. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.03.037 · Cited by 53
Dose dependent effects of cadmium on tumor angiogenesis
Wei, T., Jia, J., Wada, Y., Kapron, C. M., & Liu, J. (2017) · Oncotarget · doi:10.18632/oncotarget.16572 · Cited by 51
“Phosphorylation of eNOS leads to a flux of electrons through its reductase domain and thus facilitates the oxidative reaction in which L-arginine is transformed to L-citrulline and NO [48, 54-57].”
BackgroundDuan, Q., Song, P., Ye, D., & Zou, M. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13833 · Cited by 49
“This has been mechanistically attributed to the higher NO release by enhancing the phosphorylation and activation of endothelial NOS (eNOS) at Ser1177 and Ser633 (Chen et al., 2009; Zhang et al., 2009b) and by blocking NO inactivation by reactive oxygen species (Deng et al., 2010).”
BackgroundMuscle Insulin Resistance and the Inflamed Microvasculature: Fire from Within
Liu, J., & Liu, Z. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030562 · Cited by 49
“AMPK can functionally phosphorylate eNOS on multiple sites including Ser633 and Ser1177 to increase endothelial NO production [72,73] Activation of AMPK in addition to regulating NO production also regulates mitochondrial function and substrate metabolism as well as inhibits oxidative stress, ER stress and inflammatio…”
BackgroundAMPK α2 subunit is involved in platelet signaling, clot retraction, and thrombus stability
Randriamboavonjy, V., Isaak, J., Frömel, T., Viollet, B., Fißlthaler, B., Preissner, K. T., & Fleming, I. (2010) · Blood · doi:10.1182/blood-2010-04-279612 · Cited by 48
Metadata
- 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)
- Venue
- Circulation Research
- Published
- 2009-02-27
- Volume
- 104
- Issue
- 4
- Pages
- 496-505
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- 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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