AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633

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.

doi:10.1161/circresaha.108.187567

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

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 +3 more·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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AMPK is essential in maintaining NO bioavailability.
“Increasing evidence suggests that AMPK is essential in maintaining NO bioavailability.”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [163]
AMPK acts as a direct activator of eNOS by phosphorylating its Ser1177 residue.
“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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Background
Role of the energy sensor AMP-activated protein kinase in renal physiology and disease
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 156 · see citing works
“Activation of AMPK in endothelial cells has been reported in response to multiple and diverse stimuli, including shear stress (20), ATP depletion (95, 144), hormones such as adiponectin (18, 20, 99), bradykinin (96) and thrombin (116), the drugs metformin (143) and atorvastatin (20), and the free radical peroxynitrite…”
AMPK and NRF2: Interactive players in the same team for cellular homeostasis?
Petsouki, E., Cabrera, S. N. S., & Heiß, E. H. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.07.014 · Cited by 157 · see citing works
PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis
Yang, Q., Xu, J., Ma, Q., Liu, Z., Varadarajan, S., Cao, Y., Wang, L., Zeng, X., Zhou, Y., Zhang, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07132-x · Cited by 143 · see citing works
AMPK: A cellular metabolic and redox sensor. A minireview
Shirwany, N. A. (2014) · Frontiers in bioscience · doi:10.2741/4218 · Cited by 142 · see citing works
Acute Exposure to Low Glucose Rapidly Induces Endothelial Dysfunction and Mitochondrial Oxidative Stress
Wang, J., Alexanian, A., Ying, R., Kizhakekuttu, T. J., Dharmashankar, K., Vasquez-Vivar, J., Gutterman, D. D., & Widlansky, M. E. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.227389 · Cited by 134 · see citing works
“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).”
Influential
AMP-activated protein kinase: A remarkable contributor to preserve a healthy heart against ROS injury
Marino, A., Hausenloy, D. J., Andreadou, I., Horman, S., Bertrand, L., & Beauloye, C. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.047 · Cited by 134 · see citing works
“It has been shown that AMPK activation, in response to ONOO , enhances eNOS and NO production to restore endothelial functions [70,131].”
Background
Adiponectin as a potential biomarker of vascular disease
Mohammadi, S., Arefhosseini, S. R., Ebrahimi‐Mameghani, M., Fallah, P., & Bazi, Z. (2015) · Vascular Health and Risk Management · doi:10.2147/vhrm.s48753 · Cited by 129 · see citing works
Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes
Eringa, E. C., Serné, E. H., Meijer, R. I., Schalkwijk, C. G., Houben, A. J. H. M., Stehouwer, C. D. A., Smulders, Y. M., & van Hinsbergh, V. W. M. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9239-7 · Cited by 122 · see citing works
“AMPK regulates eNOS activity by phosphorylation at two serine residues, Ser 633 [94] and Ser 1177 [90, 95], and by stimulating the association of eNOS with heat-shock protein 90 [88].”
Background
AMPK in cardiovascular health and disease
Shirwany, N. A., & Zou, M. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.139 · Cited by 121 · see citing works
AMPK: a therapeutic target of heart failure—not only metabolism regulation
Li, X., Liu, J., Lü, Q., Ren, D., Sun, X., Rousselle, T. V., Tan, Y., & Li, J. (2018) · Bioscience Reports · doi:10.1042/bsr20181767 · Cited by 118 · see citing works
Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems
Song, P., & Zou, M. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.01.025 · Cited by 119 · see citing works
Resveratrol in Treating Diabetes and Its Cardiovascular Complications: A Review of Its Mechanisms of Action
Su, M., Zhao, W., Xu, S., & Weng, J. (2022) · Antioxidants · doi:10.3390/antiox11061085 · Cited by 120 · see citing works
AMPK-mediated regulation of transcription in skeletal muscle
McGee, S. L., & Hargreaves, M. (2010) · Clinical Science · doi:10.1042/cs20090533 · Cited by 111 · see citing works
AMPK and vasculoprotection
Ewart, M., & Kennedy, S. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.11.002 · Cited by 110 · see citing works
AMP-Activated Protein Kinase and Metabolic Control
Viollet, B., & Andréelli, F. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-17214-4_13 · Cited by 106 · see citing works
Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling
Rutherford, C., Speirs, C., Williams, J. J. L., Ewart, M., Mancini, S. J., Hawley, S. A., Delles, C., Viollet, B., Costa‐Pereira, A. P., Baillie, G. S., et al. (2016) · Science Signaling · doi:10.1126/scisignal.aaf8566 · Cited by 105 · see citing works
“However other examples of AMPK substrates that only loosely follow the optimized consensus [such as Ser 633 in endothelial constitutive nitric oxide synthase (42) ] have also been documented.”
Low-Density Lipoprotein-Cholesterol-Induced Endothelial Dysfunction and Oxidative Stress: The Role of Statins
Hermida, N., & Balligand, J. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5537 · Cited by 105 · see citing works
“…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…”
Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium
Triggle, C. R., & Ding, H. (2015) · Acta Physiologica · doi:10.1111/apha.12644 · Cited by 99 · see citing works
“Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12644 143 Ser1177 and Ser633 and enhances the generation of NO (Chen et al. 1999, 2009).”
BackgroundInfluential
SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication
Meng, T., Qin, W., & Liu, B. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.568861 · Cited by 99 · see citing works
“Except for SIRT1, AMPK has also been demonstrated to promote NO secretion by increasing eNOS phosphorylation as serine 633, which was another effective way for SIRT1 to overcome caloric restriction and facilitate vascular reconditioning after ischemia via activating the AMPK/eNOS axis (85, 86).”
Background
Atorvastatin Enhance Efficacy of Mesenchymal Stem Cells Treatment for Swine Myocardial Infarction via Activation of Nitric Oxide Synthase
Song, L., Yang, Y.-J., Dong, Q., Qian, H., Gao, R.-L., Qiao, S.-B., Shen, R., He, Z.-X., Lu, M., Zhao, S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065702 · Cited by 98 · see citing works
“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.”
Background
Activation of AMP-activated Protein Kinase by Vascular Endothelial Growth Factor Mediates Endothelial Angiogenesis Independently of Nitric-oxide Synthase
Stahmann, N., Woods, A., Spengler, K., Heslegrave, A., Bauer, R., Krause, S., Viollet, B., Carling, D., & Heller, R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.108688 · Cited by 98 · see citing works
Endothelial nitric oxide synthase: A potential therapeutic target for cerebrovascular diseases
Zhu, J., Song, W., Li, L., & Fan, X. (2016) · Molecular Brain · doi:10.1186/s13041-016-0211-9 · Cited by 96 · see citing works
The Role of PPARγ in Cardiovascular Diseases
Kvandová, M., Majzúnová, M., & Dovinová, I. (2016) · Physiological Research · doi:10.33549/physiolres.933439 · Cited by 94 · see citing works
“…protein kinases, including PKA, PKB, PKC, AMPK, ERK and phosphatases such as protein phosphatase (PP)1 and S348 Kvandová et al. Vol. 65 PP2A in response to multiple stimuli via shear stress, growth factors, insulin, etc. (Fleming et al. 2001, Mount et al. 2007, Chen et al. 2009, Xiao et al. 2011).”
Background
Coenzyme Q10 suppresses oxLDL‐induced endothelial oxidative injuries by the modulation of LOX‐1‐mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway
Tsai, K., Chen, L., Chiou, S., Chiou, G., Chen, Y., Chou, H., Chen, L., Chen, H., Chiu, T., Tsai, C., et al. (2011) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201100147 · Cited by 93 · see citing works
AMPK and cardiac remodelling
Feng, Y., Zhang, Y., & Xiao, H. (2017) · Science China Life Sciences · doi:10.1007/s11427-017-9197-5 · Cited by 89 · see citing works
Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo
Lee, R. S., Ayala, J. E., Hunley, C. F., James, F. D., Bracy, D. P., Kang, L., & Wasserman, D. H. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00004.2010 · Cited by 87 · see citing works
“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).”
Background
Resveratrol decreases fructose‐induced oxidative stress, mediated by NADPH oxidase via an AMPK ‐dependent mechanism
Cheng, P., Ho, W., Su, Y., Lu, P., Chen, B., Cheng, W., Lu, W., Sun, G., Yeh, T., Hsiao, M., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12648 · Cited by 87 · see citing works
“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).”
Background
High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway
García‐Prieto, C. F., Hernández-Nuño, F., Rio, D. D., Ruiz‐Hurtado, G., Aránguez, I., Ruiz‐Gayo, M., Somoza, B., & Fernández‐Alfonso, M. S. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201400539 · Cited by 86 · see citing works
Mechanisms underlying blood pressure reduction by dietary inorganic nitrate
Carlström, M., Lundberg, J. O., & Weitzberg, E. (2018) · Acta Physiologica · doi:10.1111/apha.13080 · Cited by 86 · see citing works
“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…”
Background
Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis
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 84 · see citing works
“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).”
Background
Fish 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 · see citing works
Perivascular fat, AMP ‐activated protein kinase and vascular diseases
Almabrouk, T. A. M., Ewart, M., Salt, I. P., & Kennedy, S. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12479 · Cited by 80 · see citing works
“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.,…”
Background
Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders
Balakumar, P., & Kathuria, S. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01938.x · Cited by 78 · see citing works
“…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).”
BackgroundInfluential
Statins in neurological disorders: An overview and update
Malfitano, A. M., Marasco, G., Proto, M., Laezza, C., Gazzerro, P., & Bifulco, M. (2014) · Pharmacological Research · doi:10.1016/j.phrs.2014.06.007 · Cited by 78 · see citing works
“[31] Chen Z, Peng IC, Sun W, Su MI, Hsu PH, Fu Y, et al.”
Background
Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase
Zheng, S., Li, W., Xu, M., Bai, X., Zhou, Z., Han, J., Shyy, J. Y.-J., & Wang, X. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00173.2010 · Cited by 79 · see citing works
“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.”
Background
Immunometabolism of AMPK in insulin resistance and atherosclerosis
Fullerton, M. D., Steinberg, G. R., & Schertzer, J. D. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.02.004 · Cited by 73 · see citing works
Translating the effects of statins: From redox regulation to suppression of vascular wall inflammation
Antonopoulos, A. S., Margaritis, M., Shirodaria, C. C., & Antoniades, C. A. (2012) · Thrombosis and Haemostasis · doi:10.1160/th12-05-0337 · Cited by 73 · see citing works
“In endothelial cells simvastatin induces eNOS Ser633 phosphorylation in an AMP-activated protein kinase (AMPK)-mediated way (37).”
Background
Therapeutic Potential of Oxytocin in Atherosclerotic Cardiovascular Disease: Mechanisms and Signaling Pathways
Wang, P., Wang, S. C., Yang, H.-P., Lv, C., Jia, S., Liu, X., Wang, X., Meng, D., Qin, D., Zhu, H. F., et al. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00454 · Cited by 73 · see citing works
How do Uremic Toxins Affect the Endothelium?
da Cunha, R. S., Santos, A. F., Barreto, F. C., & Stinghen, A. E. M. (2020) · Toxins · doi:10.3390/toxins12060412 · Cited by 72 · see citing works
“functions, including the production of nitric oxide (NO), vasodilation, and permeability [15,16].”
Background
α1AMP-Activated Protein Kinase Preserves Endothelial Function During Chronic Angiotensin II Treatment by Limiting Nox2 Upregulation
Schuhmacher, S., Foretz, M., Knorr, M., Jansen, T., Hortmann, M., Wenzel, P., Oelze, M. W., Kleschyov, A. L., Daiber, A., Keaney, J. F., et al. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.219543 · Cited by 71 · see citing works
Asiatic Acid Protects against Cardiac Hypertrophy through Activating AMPKα Signalling Pathway
Ma, Z., Dai, J., Wei, W., Zhang, W.-B., Xu, S., Liao, H.-H., Yang, Z., & Tang, Q. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.14213 · Cited by 71 · see citing works
“Previous report indicated that AA alleviated cardiovascular remodeling in rats with hypertension via restoration of eNOS expression, which has been proven a direct target of AMPKα [16, 29].”
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 70 · see citing works
AMP-activated protein kinase activator AICAR acutely lowers blood pressure and relaxes isolated resistance arteries of hypertensive rats
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 · see citing works
“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…”
Background
Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice
Enkhjargal, 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 · see citing works
“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.”
Background
Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries
Rossoni, 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 · see citing works
Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway
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 · see citing works
“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…”
BackgroundInfluential
The AMP-Activated Protein Kinase Plays a Role in Antioxidant Defense and Regulation of Vascular Inflammation
Jansen, 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 · see citing works
“Endothelium-derived NO is the key player in the regulation of the vascular tone [74,75].”
Background
Activation of the AMP-related kinase (AMPK) induces renal vasodilatation and downregulates Nox-derived reactive oxygen species (ROS) generation
Rodríguez, 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 68 · see citing works
“response to physiological stimuli such as shear stress [7,11,12] or adipokines acting via Gq receptors like adiponectin and leptin [1].”
Background
Glycocalyx sialic acids regulate Nrf2-mediated signaling by fluid shear stress in human endothelial cells
Psefteli, 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 · see citing works
“6A and B) which are critical for NO output [52, 53].”
Background
Protective 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 67 · see citing works
“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].”
Background
PPARδ 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 · see citing works
“negative Akt (Ad-DN-Akt) was described previously (33).”
Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes
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 · see citing works
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 67 · see citing works
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 66 · see citing works
“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].”
Background
Grape Seed Proanthocyanidin Extracts Enhance Endothelial Nitric Oxide Synthase Expression through 5′-AMP Activated Protein Kinase/Surtuin 1–Krüpple Like Factor 2 Pathway and Modulate Blood Pressure in Ouabain Induced Hypertensive Rats
Cui, X., Liu, X., Feng, H., Zhao, S., & Gao, H. (2012) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b12-00598 · Cited by 66 · see citing works
VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes
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 66 · see citing works
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 · see citing works
“Chen Z, et al. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633.”
Background
Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation
Chatauret, 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 · see citing works
Epithelial sodium channels in endothelial cells mediate diet-induced endothelium stiffness and impaired vascular relaxation in obese female mice
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 · see citing works
“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].”
Background
Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase
Hwang, 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 62 · see citing works
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 · see citing works
eNOS activation and NO function: Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia
Ducsay, C. A., & Myers, D. A. (2011) · Journal of Endocrinology · doi:10.1530/joe-11-0034 · Cited by 59 · see citing works
“Recently, Chen et al. (2009) showed that AMPK phosphorylates eNOS at Ser633 and is a functional signal of NO bioavailability.”
Background
Targeting 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 · see citing works
“In endothelial cells, AMPK activates eNOS via phosphorylation at Ser1177 and Ser633 (Chen et al., 1999, 2009).”
Background
Fibroblast Growth Factor 21 Protects Against High Glucose Induced Cellular Damage and Dysfunction of Endothelial Nitric-Oxide Synthase in Endothelial Cells
Wang, X., Song, S., Xiao, H., Gao, P., Li, X.-J., & Si, L. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000363031 · Cited by 58 · see citing works
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 58 · see citing works
AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension
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 · see citing works
“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”
Background
Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase
Ching, 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 · see citing works
“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).”
BackgroundResult
Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent
Ford, R. J., & Rush, J. W. E. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00597.2010 · Cited by 53 · see citing works
“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…”
BackgroundInfluential
Effects 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 · see citing works
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 · see citing works
“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].”
Background
Activation of AMP‐activated protein kinase by metformin ablates angiotensin II‐induced endoplasmic reticulum stress and hypertension in mice in vivo
Duan, Q., Song, P., Ye, D., & Zou, M. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13833 · Cited by 50 · see citing works
“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).”
Background
Muscle 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 48 · see citing works
“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…”
Background
AMPK 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 47 · see citing works

Endothelial Biology/Homeostasis: The Roles of AMPK and SIRT1 in eNOS Phosphorylation and Deacetylation
Chen, Z. (2010) · eScholarship (California Digital Library)
Direct Activation of AMP-activated Protein Kinase Stimulates Nitric-oxide Synthesis in Human Aortic Endothelial Cells
Morrow, V. A., Foufelle, F., Connell, J., Petrie, J. R., Gould, G. W., & Salt, I. P. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212831200 · Cited by 355 · see citing works
AMP‐activated protein kinase phosphorylation of endothelial NO synthase
Chen, Z.-P., Mitchelhill, K. I., Michell, B. J., Stapleton, D., Rodríguez‐Crespo, I., Witters, L. A., Power, D. A., de Montellano, P. R. O., & Kemp, B. E. (1999) · FEBS Letters · doi:10.1016/s0014-5793(98)01705-0 · Cited by 835 · see citing works
AMP-activated protein kinase is involved in endothelial NO synthase activation in response to shear stress
Zhang, Y., Lee, T.-S., Kolb, E. M., Sun, K., Lu, X., Sladek, F. M., Kassab, G. S., Garland, T., & Shyy, J. Y.-J. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000221230.08596.98 · Cited by 212 · see citing works
Modulation by Peroxynitrite of Akt- and AMP-activated Kinase-dependent Ser1179 Phosphorylation of Endothelial Nitric Oxide Synthase
Zou, M., Hou, X., Shi, C., Nagata, D., Walsh, K., & Cohen, R. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204512200 · Cited by 189 · see citing works

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 › 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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