Cited by 212Nitric Oxide and Endothelin EffectsMetabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase Signaling

The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.

AMP-Activated Protein Kinase Is Involved in Endothelial NO Synthase Activation in Response to Shear Stress

Zhang, Yingjia, Lee, Tzong-Shyuan, Kolb, Erik M., Sun, Kai, Lu, Xiao, Sladek, Frances M., Kassab, Ghassan S., Garland, Theodore, Shyy, John Y.-J.·2006·Arteriosclerosis Thrombosis and Vascular Biology

DOI 10.1161/01.atv.0000221230.08596.98

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Abstract

OBJECTIVE: The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK-eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner). METHODS AND RESULTS: By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice. CONCLUSIONS: Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.

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BackgroundResult
AMP-Activated Protein Kinase α1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo
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Background
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“…fitness is associated with AMPK and Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha activation, which in turn, stimulates endothelial nitric oxide synthase in response to shear stress of vascular endothelial cells (Kim, Lee, Kawata, & Park, 2014; Zhang et al., 2006).”
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Portulaca Oleracea L. (Purslane) Extract Protects Endothelial Function by Reducing Endoplasmic Reticulum Stress and Oxidative Stress through AMPK Activation in Diabetic Obese Mice
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Background
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Background
Hyaluronidase2 (Hyal2) modulates low shear stress‐induced glycocalyx impairment via the LKB1/AMPK/NADPH oxidase‐dependent pathway
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Background
EDF-1 contributes to the regulation of nitric oxide release in VEGF-treated human endothelial cells
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“While nitrite levels are maintained in the body, variability between individuals is due to differences that may be due to dietary habits, physical exercise (235), tobacco use (168), and cardiovascular dysfunction (212, 213).”
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Background
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“Shortly after, it was shown that the activity of the upstream kinase LKB1 increased after BAECs were exposed to LSS and that LKB1 immunoprecipitated with GST-AMPK with resulting eNOS phosphorylation, suggesting a shear-responsive LKB1-AMPK-eNOS pathway in ECs [72].”
Background
Omics‐based approaches to understand mechanosensitive endothelial biology and atherosclerosis
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“Specifically, AMPK Thr172 phosphorylation was increased with shear stress in cultured ECs as well as the phosphorylation of eNOS at Ser1179.”
Background
c-Jun N-terminal kinase 2 phosphorylates endothelial nitric oxide synthase at serine 116 and regulates nitric oxide production
Park, J., Park, M., Byun, C. J., & Jo, I. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.112 · Cited by 18
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Mitochondrial DNA integrity and function are critical for endothelium-dependent vasodilation in rats with metabolic syndrome
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Fenofibrate Enhances Neovascularization in a Murine Ischemic Hindlimb Model
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“The NO molecular pathway and its role in angiogenesis has been well investigated in endothelial cells, and our results are most likely explained by a similar mechanism involving activation of the Akt protein kinase and 5#-adenosine monophosphate-activated protein kinase(7) and phosphorylation of Ser1177 in endothelial…”
BackgroundResult
Metformin regulates differentiation of bone marrow-derived endothelial progenitor cells via multiple mechanisms
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“[10-12] Laminar and/or pulsatile shear stress is potent stimuli to induce KLF4 in ECs.”
BackgroundInfluential
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“Upstream to eNOS, activated AMPK (phosphorylation at threonine 172) phosphorylates eNOS at serine 1177 to promote NO production [24].”
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Activation of the AMP-Activated Protein Kinase (AMPK) by Nitrated Lipids in Endothelial Cells
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Retracted
A 6 hour therapeutic window, optimal for interventions targeting AMPK synergism and apoptosis antagonism, for cardioprotection against myocardial ischemic injury: an experimental study on rats.
Ma, M., Thapalia, B. A., & Lin, X. (2015) · Europe PMC (PubMed Central) · Cited by 14
Shear Stress and Metabolic Disorders—Two Sides of the Same Plaque
Jiang, M., Ding, H., Huang, Y., & Wang, L. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0126 · Cited by 12
“As another response to shear stress, AMPK plays a crucial role in the regulation of vascular tone by elevating eNOS activity and the subsequent NO production (201).”
Atheroprotective Pulsatile Flow Induces Ubiquitin-Proteasome–Mediated Degradation of Programmed Cell Death 4 in Endothelial Cells
Cheng, G., Song, J., Chen, L., Wang, L., Chen, Y., Liu, X., Zhang, Y., Zhang, L., & Zhang, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091564 · Cited by 13
“We examined the expression of p21 , a cyclin-dependent kinase inhibitor that suppresses cell proliferation [23]; cleaved or active caspase-3, the final executioner of most apoptosis [24]; and phosphorylated endothelial nitric oxide (NO) synthase (eNOS), the key enzyme for NO production in endothelial cells that mainta…”
Background
Mechanical Stretch and Cytokines
Henrotin, Y., Pesesse, L., & Sanchez, C. (2011) · Springer eBooks · doi:10.1007/978-94-007-2004-6 · Cited by 14
A versatile microfluidic device for multiple ex vivo/in vitro tissue assays unrestrained from tissue topography
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Molecular mechanisms of the vascular responses to hemodynamic forces
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Aortic waveform responses to insulin in late versus early chronotype with metabolic syndrome
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“This is also consistent with others showcasing that fitness enhances endothelial nitric oxide (NO) bioavailability (Kim et al., 2014; Zhang et al., 2006).”
Result
Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective
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The Potential of Gamma Secretase as a Therapeutic Target for Cardiac Diseases
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Quercetin intake during lactation modulates the AMP-activated protein kinase pathway in the livers of adult male rat offspring programmed by maternal protein restriction
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“In addition, AMPK phosphorylates and activates endothelial nitric oxide synthase (eNOS) in endothelial cells [7,8].”
Background
Green Tea Extract Increases mRNA Expression of Enzymes Which Influence Epigenetic Marks in Newborn Female Offspring from Undernourished Pregnant Mother
Sun, Y., Mukai, Y., Tanaka, M., Saito, T., Sato, S., & Kurasaki, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074559 · Cited by 9
“Because AMPK is reported to be associated with the phosphorylation of eNOS, resulting in an increased release of NO [27,28], we investigated the expression and phosphorylation of eNOS.”
Background
S‑1‑Propenylcysteine, a sulfur compound in aged garlic extract, alleviates cold‑induced reduction in peripheral blood flow in rat via activation of the AMPK/eNOS/NO pathway
Ushijima, M., Kunimura, K., & Suzuki, J. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8969 · Cited by 8
“AMPK is known to phosphorylate the specific serine residue (Ser1177) of eNOS that is essential for its activation (58,59).”
TNFα stimulates NO release in EA.hy926 cells by activating the CaMKKβ-AMPK-eNOS pathway
Dymkowska, D., Drabarek, B., Michalik, A., Nowak, N., & Zabłocki, K. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.11.010 · Cited by 8
Shear Stress Modulates Resistin‐Induced CC Chemokine Ligand 19 Expression in Human Aortic Endothelial Cells
Yu, H., Sung, M., Kuo, H., Lin, C., & Chen, C. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.24940 · Cited by 8
“ECs that are subjected to high-shear stress also exhibit anti-inflammatory properties by activation of atheroprotective proteins such as AMP-activated protein kinase or endothelial nitric oxide synthase (eNOS) (Zhang et al., 2006; Young et al., 2009).”
Background
Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury
Mutchler, S. M., Hasan, M., Kohan, D. E., Kleyman, T. R., & Tan, R. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222010914 · Cited by 7
“Shear stress-induced mechanical deformation can cause this phosphorylation and activation of eNOS in endothelial cells through increases in calcium signaling [11,12].”
Background
Autophagy-urea cycle pathway is essential for the statin-mediated nitric oxide bioavailability in endothelial cells
Chen, W., Guo, B., Chen, C., Hsu, M., Wang, C., & Lee, T. (2023) · Journal of Food and Drug Analysis · doi:10.38212/2224-6614.3472 · Cited by 6
“In addition to its crucial role in autophagy activation, AMPK is also involved in shear stressinduced eNOS activation and NO bioavailability [8].”
Background
Subcellular Targeting of Nitric Oxide Synthases Mediated by Their N-Terminal Motifs
Costas‐Insua, C., Merino, J., Aicart-Ramos, C., & Rodríguez‐Crespo, I. (2017) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2017.07.002 · Cited by 5
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Ultrasound-Stimulated Microbubbles Cavitation Combined with Nitric Oxide Signaling Pathway to Alleviate Tumor Hypoperfusion and Hypoxia in MC38 Tumor Model
Luo, T., Lei, Y., Wu, Y. P., Zhang, Y., Lian, L., He, P. L., Li, N., Dong, X., & Liu, Z. (2025) · Academic Radiology · doi:10.1016/j.acra.2025.03.034 · Cited by 5
Mechanical forces orchestrate the epigenetic landscape of oral mesenchymal stem/progenitor cell fate in dental and periodontal tissues
Zhou, Y., Zhang, G., & He, H. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1743397 · Cited by 4
“While AMPK-dependent phosphorylation of PFKFB3 and endothelial nitric-oxide synthase further amplifies glycolytic flux (De Bock et al., 2013; Zhang et al., 2006; Doménech et al., 2015).”
Lysyl-tRNA synthetase 1 promotes atherogenesis via autophagy-related secretion and inflammation
Yun, K., Seo, Y., Oh, Y., Kim, S., Maeng, H. S., Cho, J. G., Son, Y. B., Son, D. J., Kwon, K., Kim, S., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-96046-y · Cited by 5
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B56δ subunit of protein phosphatase 2A decreases phosphorylation of endothelial nitric oxide synthase at serine 116: Mechanism underlying aphidicolin-stimulated NO production
Park, J., Cho, D., Lee, J. Y., Lee, H.-J., Ha, Y.-N., Ahn, J., & Jo, I. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.08.001 · Cited by 4
Activation of ATM/Akt/CREB/eNOS Signaling Axis by Aphidicolin Increases NO Production and Vessel Relaxation in Endothelial Cells and Rat Aortas
Park, J., Cho, D., Hwang, Y., Lee, J. Y., Lee, H.-J., & Jo, I. (2020) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2020.007 · Cited by 4
“Phosphorylation of these sites is regulated by various stimuli and contributes to acute endothelial NO production and vascular tone (Kou et al., 2002; Bae et al., 2003; Cho et al., 2004; Zhang et al., 2006; Park et al., 2011; Cho et al., 2014).”
Background
Mechanical Stretching of Cells of Different Tissues: The Role of Mediators of Innate Immunity
Ковальчук, Л. В., Хорева, М. В., Nikonova, A. S., Kazansky, V. E., Lozinsky, I. T., D’iakonova, I. N., & Kamkin, A. G. (2011) · Springer eBooks · doi:10.1007/978-94-007-2004-6_2 · Cited by 4
Adrenomedullin-RAMP2 Enhances Lung Endothelial Cell Homeostasis Under Shear Stress
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Authors: Zhang, Y., Lee, T.-S., Kolb, E. M., Sun, K., Lu, X., Sladek, F. M., Kassab, G. S., Garland, T., & Shyy, J. Y.-J.
Affiliations: University of California, Riverside (US)
ORCID: Lee, Tzong-Shyuan
Sun, Kai
Lu, Xiao
Sladek, Frances M.
Kassab, Ghassan S.
Garland, Theodore
Venue: Arteriosclerosis Thrombosis and Vascular Biology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-06
Volume: 26
Issue: 6
Pages: 1281-1287
ISSN: 1079-5642 (ISSN-L)
1524-4636
DOI: 10.1161/01.atv.0000221230.08596.98
OpenAlex: W2143950284
Cited by: 212
References: 35
Citations by year: 2026: 7 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 11 · 2021: 15 · 2020: 11 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 8 · 2015: 11 · 2014: 12 · 2013: 17 · 2012: 8
FWCI: 9.28
Type: journal article
Language: en
Open access: closed
Locations: Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
PubMed (publishedVersion)
Funders: National Heart, Lung, and Blood Institute (HL-77448, HL55554, R01HL077448)
National Institute of Diabetes and Digestive and Kidney Diseases (DK053892, R01DK053892)
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, shear stress, endothelial cells, LKB1, nitric oxide production, vascular tone, voluntary running, aorta, pulsatility, flow rate
MeSH terms: Animals, Aorta, Cattle, Cells, Cultured, Motor Activity, Multienzyme Complexes, Nitric Oxide, Phosphorylation, Protein Kinases, Pulsatile Flow, Stress, Mechanical, Protein Serine-Threonine Kinases, Endothelial Cells, Mice, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases

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AMP-Activated Protein Kinase Is Involved in Endothelial NO Synthase Activation in Response to Shear Stress

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