Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress
Abstract
Laminar shear stress (LSS) is a protective hemodynamic regulator of endothelial function and limits the development of atherosclerosis and other vascular wall diseases related to pathophysiological generation of reactive oxygen species. LSS activates several endothelial signaling responses, including the activation of MAPKs and eNOS. Here, we explored the mechanisms of activation of these key endothelial signaling pathways. Using the cone/plate model we found that LSS (12 dyn/cm(2)) rapidly promotes endothelial intracellular generation of superoxide and hydrogen peroxide (H(2)O(2)). Physiological concentrations of H(2)O(2) (flux of 0.1 nM/min and 15 μM added extracellularly) significantly activated both eNOS and p38 MAPK. Pharmacological inhibition of NADPH oxidases (NOXs) and specific knockdown of NOX4 decreased LSS-induced p38 MAPK activation. Whereas the absence of eNOS did not alter LSS-induced p38 MAPK activation, pharmacological inhibition and knockdown of p38α MAPK blocked H(2)O(2)- and LSS-induced eNOS phosphorylation and reduced (•)NO levels. We propose a model in which LSS promotes the formation of signaling levels of H(2)O(2), which in turn activate p38α MAPK and then stimulate eNOS, leading to increased (•)NO generation and protection of endothelial function.
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The signaling mechanisms of hydrogen peroxide in ECs lead to the increased activity of eNOS and other enzymes.
“The signaling mechanisms of hydrogen peroxide in ECs (941) lead to the increased activity of eNOS and other enzymes (121, 141, 193, 251, 815, 940).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [121]
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“The H 2 O 2 formed in these conditions is possibly activating eNOS, 45 given that FID is fully diminished following eNOS inhibition.”
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“Iako je iznenadna okluzija krvnog suda izazvana tromboembolijskim događajima najčešći uzrok ishemičnog oštećenja mozga [2], primećeno je da tokom operativnih zahvata kao što je karotidna endarterektomija (CEA; engl.”
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- Authors
- Bretón-Romero, R., González de Orduña, C., Romero, N., Sánchez-Gómez, F. J., de Álvaro, C., Porras, A., Rodríguez-Pascual, F., Laranjinha, J., Radi, R., & Lamas, S.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Lamas, Santiago
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 52
- Issue
- 6
- Pages
- 1093-1100
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2038538108
- Cited by
- 66
- References
- 60
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 10 · 2016: 2 · 2015: 10 · 2014: 7 · 2013: 8 · 2012: 2
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- laminar shear stress, hydrogen peroxide signaling, p38 MAPK, endothelial nitric oxide synthase, endothelial function, NADPH oxidase, NOX4, superoxide, nitric oxide, reactive oxygen species, atherosclerosis, MAPK signaling
- MeSH terms
- NADPH Oxidase 4, Animals, Cattle, Cell Line, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Hemodynamics, Hydrogen Peroxide, Regional Blood Flow, Stress, Mechanical, Signal Transduction, Mice, Knockout, NADPH Oxidases, Shear Strength, RNA, Small Interfering, p38 Mitogen-Activated Protein Kinases, Atherosclerosis, Mice, Nitric Oxide Synthase Type III
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