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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Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo
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Background
A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis
Xu, S., Liu, B., Yin, M., Королева, М. В., Mastrangelo, M. A., Ture, S. K., Morrell, C. N., Zhang, D. X., Fisher, E. A. A., & Jin, Z. G. (2016) · Oncotarget · doi:10.18632/oncotarget.9376 · Cited by 68
“A, GSK1016790A (GSK101) increases AMPK activation.”
Influential
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 70
Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation
Jin, Y., Chennupati, R., Li, R., Liang, G., Wang, S., Iring, A., Graumann, J., Wettschureck, N., & Offermanns, S. (2021) · Journal of Clinical Investigation · doi:10.1172/jci145734 · Cited by 70
“Later, other related protein kinases, including AMP-activated kinase (AMPK) and PKA have been reported to be also able to mediate flow-induced eNOS phosphorylation at serine 1177 (4, 5, 13, 14).”
Background
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
Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System
Choi, Y. K., & Kim, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137041 · Cited by 65
“In experiments on flow channels in cultured endothelial cells, AMPKα phosphorylation was increased with changes in the flow rate or pulsatility [91].”
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
Activation of the AMP-Activated Protein Kinase by Eicosapentaenoic Acid (EPA, 20:5 n-3) Improves Endothelial Function In Vivo
Wu, Y., Zhang, C., Dong, Y., Wang, S., Song, P., Viollet, B., & Zou, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035508 · Cited by 64
“[28] demonstrated that infection of endothelial cells with a recombinant adenovirus expressing the constitutively active AMPK results in eNOS activation and increased NO production.”
Background
Nitric oxide generation by endothelial cells exposed to shear stress in glass tubes perfused with red blood cell suspensions: role of aggregation
Yalçın, Ö., Ülker, P., Yavuzer, U., Meiselman, H. J., & Baskurt, O. K. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00015.2008 · Cited by 64
“on February 15, 2010 ajpheart.physiology.org Downloaded from synthesis (30) and eNOS phosphorylation (7, 48 ).”
Background
Niacin bound chromium treatment induces myocardial Glut-4 translocation and caveolar interaction via Akt, AMPK and eNOS phosphorylation in streptozotocin induced diabetic rats after ischemia-reperfusion injury
Penumathsa, S. V., Thirunavukkarasu, M., Samuel, S. M., Zhan, L., Maulik, G., Bagchi, M., Bagchi, D., & Maulik, N. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.10.018 · Cited by 63
Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide Synthesis and Microvascular Perfusion
Bradley, E. A., Eringa, E. C., Stehouwer, C. D. A., Korstjens, I. J. M., Amerongen, G. P. V. N., Musters, R. J. P., Sipkema, P., Clark, M. G., & Rattigan, S. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.204404 · Cited by 62
AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6
Gongol, B., Marin, T., Peng, I.-C., Woo, B., Martin, M., King, S., Sun, W., Johnson, D. A., Chien, S., & Shyy, J. Y.-J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222051110 · Cited by 61
“In particular, pulsatile flow (PS) activates AMPK (25) and is associated with anti-inflammatory effects (6– 9).”
Background
Far-infrared radiation acutely increases nitric oxide production by increasing Ca2+ mobilization and Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of endothelial nitric oxide synthase at serine 1179
Park, J., Lee, S., Cho, D., Park, Y. M., Kang, D., & Jo, I. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.06.003 · Cited by 59
A protective role of ciglitazone in ox‐ LDL ‐induced rat microvascular endothelial cells via modulating PPAR γ‐dependent AMPK / eNOS pathway
Xu, L., Wang, S., Li, B., Sun, A., Zou, Y., & Ge, J. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12463 · Cited by 55
“Metformin, the AMPK activator, proved to be effective in meditating vascular protection against calcification, improving myocardial infarction and attenuating ventricular hypertrophy, all of which required the mechanism of AMPK-dependent eNOS activation [26, 29, 42, 43].”
Background
Resveratrol prevents hyperglycemia-induced endothelial dysfunction via activation of adenosine monophosphate-activated protein kinase
Xu, Q., Hao, X., Yang, Q., & Si, L. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.08.021 · Cited by 56
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
“For instance, shear stress, the major physiological stimulation in the vascular system, was found to activate AMPK, which in turn phosphorylated eNOS at Ser635 and Ser1179, thus leading to enhanced NO bioavailability (27,36).”
Background
Atheroprone flow enhances the endothelial-to-mesenchymal transition
Lai, B., Li, Z., He, M., Wang, Y., Chen, L., Zhang, J., Yang, Y., & Shyy, J. Y.-J. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00213.2018 · Cited by 53
Roles of KLF4 and AMPK in the inhibition of glycolysis by pulsatile shear stress in endothelial cells
Han, Y., He, M., Marin, T., Shen, H., Wang, W., Lee, T.-Y., Hong, H.-C., Jiang, Z., Garland, T., Shyy, J. Y.-J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2103982118 · Cited by 53
“We used adult males from a selectively bred mouse model (generation 83) with a high level of voluntary wheel running, namely, high-runner (HR) mice (28), to substantiate the finding that KLF4-AMPK/GCKR inhibits glycolysis in the endothelium in vivo.”
BackgroundMethodInfluential
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
“Although recognized primarily as a modulator of cellular energy status and metabolism (28, 57), the identification of its existence in vascular cells and of its ability to be stimulated by numerous physical (8, 20, 59), energetic (17), hormonal (5, 8, 43), and chemical (8, 9, 11, 12, 29, 35, 40, 53) mediators of vasom…”
Background
Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity
DiNicolantonio, J. J., McCarty, M. F., Assanga, S. B. I., Luján, L. M. L., & O’Keefe, J. H. (2022) · Open Heart · doi:10.1136/openhrt-2021-001801 · Cited by 54
Cardioprotective effects of nitrite during exercise
Calvert, J. W. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq307 · Cited by 51
“Exercise has been associated with increasing plasma nitrite levels in both rodents and humans.(9,75,76) However, the increased circulating levels of nitrite have traditionally been considered only as an acute marker of NO production and a surrogate for endothelial function.”
Background
Defective Metabolic Signaling in Adenylate Kinase AK1 Gene Knock-out Hearts Compromises Post-ischemic Coronary Reflow
Dzeja, P. P., Bast, P., Pucar, D., Wieringa, B., & Terzic, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705268200 · Cited by 50
Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation
Tanaka, L. Y., & Laurindo, F. R. M. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.025 · Cited by 49
Protein kinase N2 mediates flow-induced eNOS activation and vascular tone regulation
Jin, Y., Chennupati, R., Li, R., Liang, G., Wang, S., & Iring, A. (2021) · Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) · Cited by 49
Globular adiponectin inhibits angiotensin II‐induced nuclear factor κB activation through AMP‐activated protein kinase in cardiac hypertrophy
Wang, C., Li, L., Zhang, Z., Dong, F., Zhu, Y., & Wu, L. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21931 · Cited by 47
“This Ad-AMPK-DN inhibits endogenous AMPK activity by replacing the endogenous AMPKa subunit JOURNAL OF CELLULAR PHYSIOLOGY with the inactive form in the abg homoenzyme (Zhang et al., 2006).”
Method
Prostaglandin E2 Promotes Endothelial Differentiation from Bone Marrow-Derived Cells through AMPK Activation
Zhu, Z., Fu, C., Li, X., Song, Y., Li, C., Zou, M., Guan, Y., & Zhu, Y. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023554 · Cited by 48
“Ad-AMPK-DN, a recombinant adenovirus expressing a dominant-negative mutant of AMPK, was described previously [15].”
Background
Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating amp-activated protein kinase
Dong, Q., Yang, Y., Song, L., Qian, H., & Xu, Z.-M. (2010) · International Journal of Cardiology · doi:10.1016/j.ijcard.2010.08.047 · Cited by 47
Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death
Nakatsu, Y., Kotake, Y., Hino, A., & Ohta, S. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.03.021 · Cited by 48
“Involvement of AMPK in nitric oxide synthase (NOS) activation NOS activation is reported to be downstream of AMPK (Zhang et al., 2006).”
Background
Activation of AMPK/miR-181b Axis Alleviates Endothelial Dysfunction and Vascular Inflammation in Diabetic Mice
Cheng, C. K., Shang, W., Liu, J., Cheang, W. S., Wang, Y., Li, X., Lau, C., Luo, J., Ng, C., Huang, Y., et al. (2022) · Antioxidants · doi:10.3390/antiox11061137 · Cited by 47
“Additionally, LSS promotes AMPK activation in endothelial cells [54].”
Background
Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress–related AMPK/FoxO1 signaling
Richter, R. P., Ashtekar, A. R., Zheng, L., Pretorius, D., Tripathi, K. K., Sanderson, R. D., Gaggar, A., & Richter, J. R. (2022) · JCI Insight · doi:10.1172/jci.insight.155010 · Cited by 48
“(46) showed that eNOS activity may also be controlled by AMPK signaling.”
Background
AMP‐activated protein kinase mediates erythropoietin‐induced activation of endothelial nitric oxide synthase
Su, K., Yu, Y., Hou, H., Zhao, J., Kou, Y. R., Cheng, L., Shyue, S., & Lee, T. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.23052 · Cited by 45
“Furthermore, arterial AMPK activity and phosphorylation of eNOS were found increased in exercisetraining mice (Zhang et al., 2006; Zhang et al., 2009).”
Background
Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity
Vaanholt, L. M., Jónás, I., Doornbos, M. E., Schubert, K. A., Nyakas, C. J., Garland, T., Visser, G. H., & van Dijk, G. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.136 · Cited by 44
Vinegar as a functional ingredient to improve postprandial glycemic control—human intervention findings and molecular mechanisms
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Flow-Mediated Signaling Modulates Endothelial Cell Phenotype
Garin, G., & Berk, B. C. (2006) · Endothelium · doi:10.1080/10623320601061599 · Cited by 44
Anthracycline chemotherapy‐mediated vascular dysfunction as a model of accelerated vascular aging
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Exercise performance and peripheral vascular insufficiency improve with AMPK activation in high-fat diet-fed mice.
Baltgalvis, K. A., White, K., Li, W., Claypool, M. D., Lang, W., Alcantara, R. R., Singh, B., Friera, A. M., McLaughlin, J. R., Hansen, D., et al. (2014) · American Journal of Physiology. Heart and Circulatory Physiology · doi:10.1152/ajpheart.00839.2013 · Cited by 41
Targeting the vasculature in cardiometabolic disease
Boutagy, N. E., Singh, A. K., & Sessa, W. C. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148556 · Cited by 45
“Interestingly, in ECs, AMPK activation was demonstrated to activate eNOS (99, 100), thus supporting a bidirectional relationship between energy sensing and NO signaling.”
Background
LKB1 Deficiency in Tie2-Cre-expressing Cells Impairs Ischemia-induced Angiogenesis
Ohashi, K., Ouchi, N., Higuchi, A., Shaw, R. J., & Walsh, K. X. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123794 · Cited by 43

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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