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AMP-Activated Protein Kinase Is Involved in Endothelial NO Synthase Activation in Response to Shear Stress
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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“As discussed previously, a similar general outcome of metformin, AICAR, atheroprotective flow, and statins on ECs can be found through AMPK activation [245,250,251].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [245]
In the citing paper
“Metformin has been proven as an anti-inflammatory, especially for the inflammation in diabetes and following postsurgical endotoxin [245,246,247].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [245]
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“Some evidence indicates that cells are sensitive to features of pulsatile flow (23, 24), though more systematic studies of these effects are needed.”
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“Moreover, the interpretation of the protective effects of AMPK and HIF through the NO-driven modulation of the mitochondrial respiratory chain are further complicated by the recently described AMPK-dependent activation of eNOS (243, 367, 449).”
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Metadata
- 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)
- Venue
- Arteriosclerosis Thrombosis and Vascular Biology
- Published
- 2006-06
- Volume
- 26
- Issue
- 6
- Pages
- 1281-1287
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- 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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