Cited by 142Nitric Oxide and Endothelin EffectsTea Polyphenols and EffectsPhytochemicals and Antioxidant Activities

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Activation of Endothelial Nitric-oxide Synthase by the p38 MAPK in Response to Black Tea Polyphenols

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Anter, Elad, Thomas, Shane R., Schulz, Eberhard, Shapira, Oz M., Vita, Joseph A., Keaney, John F.·2004·Journal of Biological Chemistry

DOI 10.1074/jbc.m405547200

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Abstract

Black tea improves endothelial function in patients with coronary artery disease. We sought to determine the responsible components of black tea and elucidate the underlying cell signaling mechanisms. We exposed porcine aortic endothelial cells to components of black tea and found that the polyphenol fraction acutely enhanced nitric oxide bioactivity. This effect involved endothelial nitric-oxide synthase (eNOS) phosphorylation at Ser-1177 and dephosphorylation at Thr-495, consistent with increased eNOS activity. These effects were calcium-dependent, as removal of extracellular calcium prevented eNOS phosphorylation at Ser-1177, whereas inhibition of intracellular calcium mobilization with TMB-8 blunted Thr-495 dephosphorylation. Black tea polyphenol-induced eNOS activation appeared dependent upon the phosphatidylinositol 3-kinase-Akt pathway, as it was significantly inhibited by LY294002 and a dominant negative Akt, respectively. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38 MAPK) with either SB202190 or SB203580 as well as overexpression of a dominant negative p38 MAPKalpha attenuated both eNOS activation and phosphorylation changes in response to black tea polyphenols. Inhibition of p38 MAPKalpha also blunted Akt activation in response to black tea polyphenols, suggesting that p38alpha MAPK is upstream of Akt in this pathway. Finally, a constitutively active mutant of MKK6bE, an upstream kinase for p38 MAPK, enhanced both the basal and stimulated activity of Akt, leading to increased eNOS activity. Taken together, these data identify the p38 MAPK as an upstream component of Akt-mediated eNOS activation.

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“Similar interaction between the PI3K/Akt and p38 MAPK pathways has recently been described in aortic endothelial cells.(40) Taken together, our results indicated that abrogation of the antiapoptotic effect of OV required Bad dephosphorylation at both serine residues and thus suggested that phosphorylation of Bad eithe…”
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“Because phosphorylation of eNOS at ser1177 indicates enzyme activation by MAPK and the AKT (Anter et al., 2004), we examined the ratio of P-ser1177- eNOS/total eNOS after treatment of HUVEC with E 2 or DEPE.”
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“…al., 2003) where it is phosphorylated and fully activated by protein kinases that reside in caveolae such as p38 mitogen-activated protein kinase (Anter et al., 2004) phosphatidylinositol 3-kinase-Akt (Anter et al., 2004; Uruno et al., 2005), cAMP-dependent protein kinase A, and AMPK (Tanano et…”
Background
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Garza, A. E., Pojoga, L. H., Moize, B., Hafiz, W. M., Opsasnick, L. A., Siddiqui, W. T., Horenstein, M., Adler, G. K., Williams, G. H., & Khalil, R. A. (2015) · Hypertension · doi:10.1161/hypertensionaha.115.05600 · Cited by 31
“An increase in endothelial cell Ca by ACh induces the release of eNOS from cav-1 to the cytosol(19,20) where it is phosphorylated and fully activated by mitogenactivated protein kinase and phosphatidylinositol 3-kinaseAkt..(21,22) Activated eNOS converts l-arginine to l-citrulline and increases NO release.”
Background
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“Black tea polyphenols also induced the formation of NO through a calcium-dependent mechanism involving both intracellular and extracellular calcium, and the p38 mitogen-activated protein kinase (MAPK) pathway upstream of the PI3-kinase/Akt pathway leading to the phosphorylation of eNOS at Ser 1177 and the dephosphoryl…”
Background
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“The recent work has identified p38 MAPK as an upstream mediator of Akt-dependent eNOS activation in endothelial cells (Anter et al., 2004).”
Background
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“In addition, black tea extracts exposed to porcine aortic endothelial cells could significantly boost the bioactivity of NO in aortic endothelial cells (37).”
Background
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Wang, M., Bai, Y., Wang, Z., Zhang, Z., Liu, D., & Lian, X. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.08.039 · Cited by 26
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“…on the role of ERK1/2 and p38 MAPK in the phosphorylation of eNOS are controversial (Bernier et al., 2000; Wang et al., 2001; Schmidt et al., 2002; Anter et al., 2004), coactivation of eNOS, ERK1/ 2, and p38 MAPK have been reported to occur during exposure of endothelium to VEGF (Rousseau et al.,…”
Background
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“Polyphenols are suggested to increase calcium-dependent endothelium nitric oxide synthase (eNOS) phosphorylation through the phosphatidylinositol 3-kinase-Akt pathway (3), thus enhancing NO production.”
Background
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“There is in vitro evidence for changes in the phosphorylation pattern of endothelial nitric oxide synthase (eNOS) in response to tea polyphenols [25].”
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“JNK has been implicated in modulating a variety of endothelial functions, such as VEGF signaling, angiogenesis, and NO bioactivity (Anter et al., 2004; Du et al., 2013; Guma et al., 2009; Lamalice et al., 2004; Matsumoto et al., 2002).”
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“In line with our findings, others have already shown that E2 facilitates both the expression of eNOS and its activity in endothelial cells, effects that are E2-specific because they are inhibited by ER blockade [2].”
Result
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Shafique, M. S., & Divakar, C. (2011) · Cited by 21
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“This stimulatory effect was calcium dependent, involving both intracellular and extracellular calcium and involved the p38 MAPK upstream of PI3-kinase/Akt pathway [1].”
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Telmisartan Activates Endothelial Nitric Oxide Synthase via Ser1177 Phosphorylation in Vascular Endothelial Cells
Myojo, M., Nagata, D., Fujita, D., Kiyosue, A., Takahashi, M., Satonaka, H., Morishita, Y., Akimoto, T., Nagai, R., Komuro, I., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096948 · Cited by 17
“Materials Antibodies against phospho-eNOS (Ser1177), phosphoAMPKa (Thr172), AMPKa, phospho-Akt (Ser473), phosphop38 mitogen-activated protein kinase (p38 MAPK) (Thr180/ Tyr182), p38 MAPK and cAMP response element binding protein (CREB) were purchased from Cell Signaling Technology (Danvers, MA).”
BackgroundInfluential
Health-Promoting Effects of Wine Phenolics
Dávalos, A., & Lasunción, M. A. (2008) · Springer eBooks · doi:10.1007/978-0-387-74118-5_25 · Cited by 18
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“Another probable mechanism of action of LA involves activation of mitogen-activated protein kinase, which in turn will upregulate eNOS and increase NO production [31].”
Background
Mediterranean Diet and Health Promotion: evidence and current concerns
Ciancarelli, M. G. T., Massimo, C. D., Amicis, D. D., & Ciancarelli, I. (2017) · Medical Research Archives · doi:10.18103/mra.v5i7.1385 · Cited by 15
Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells
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“01, n = 4 experiments; (C) The enhanced Ach-induced vasorelaxation responses in aortic vessels of ArgII−/− mice were attenuated with p38 MAPK inhibitor, but sodium nitroprusside (SNP) responses did not differ among the groups (D); (E) PE-induced constrictive responses were enhanced in p38 MAPK inhibitor-treated aortic…”
BackgroundMethodInfluential
Polyphenol-rich Aronia melanocarpa juice sustains eNOS activation through phosphorylation and expression via redox-sensitive pathways in endothelial cells
Kim, J. H., Choi, M. S., Auger, C., Lee, K. W., & Schini‐Kerth, V. B. (2024) · Food Science and Biotechnology · doi:10.1007/s10068-024-01546-8 · Cited by 10
“In another previous study, it was also reported that p38 MAPK is upstream of Akt-eNOS pathway (Anter et al., 2004).”

Authors: Anter, E., Thomas, S. R., Schulz, E., Shapira, O. M., Vita, J. A., & Keaney, J. F.
Affiliations: Boston University (US)
Corresponding author: Keaney, John F.
ORCID: Anter, Elad
Thomas, Shane R.
Schulz, Eberhard
Shapira, Oz M.
Vita, Joseph A.
Keaney, John F.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2004-11
Volume: 279
Issue: 45
Pages: 46637-46643
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m405547200
OpenAlex: W1998394852
Cited by: 142
References: 37
Citations by year: 2026: 2 · 2024: 5 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 11
FWCI: 5.34
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5833 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01dk055656-03)
National Heart, Lung, and Blood Institute (K02HL067206, P01HL060886, HL68758, HL 67206, P01HL068758, HL-60886)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-55656)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Agricultural and Biological Sciences › Food Science › Tea Polyphenols and Effects
Health Sciences › Medicine › Biochemistry (medical) › Phytochemicals and Antioxidant Activities
Keywords: black tea polyphenols, endothelial nitric oxide synthase, p38 MAPK, Akt signaling, eNOS phosphorylation, nitric oxide bioactivity, endothelial function, phosphatidylinositol 3-kinase, calcium signaling, coronary artery disease, porcine aortic endothelial cells
MeSH terms: Adenoviridae, Animals, Aorta, Arginine, Calcium, Calmodulin, Catalysis, Citrulline, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Flavonoids, Genetic Vectors, Imidazoles, Mutation, Nitric Oxide, Phenols, Phosphorylation, Pyridines, Swine, Tea, Time Factors, Transfection, Blotting, Western, Signal Transduction, Nitric Oxide Synthase, Phosphatidylinositol 3-Kinases, Immunoprecipitation, p38 Mitogen-Activated Protein Kinases, Nitric Oxide Synthase Type III, Polyphenols

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Activation of Endothelial Nitric-oxide Synthase by the p38 MAPK in Response to Black Tea Polyphenols

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