Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1
Open accessAbstract
Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO) and endothelin-1 (ET-1), respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These effects were related to positive modulation of insulin signaling, which via PI3K/Akt is a critical regulator of eNOS phosphorylation and activity.
“These effects were related to a positive modulation of insulin signaling, that, via PI3K/Akt, is considered a critical regulator of eNOS phosphorylation and activity [199].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [199]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
2 retracted
RETRACTED: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet
Estruch, R., Ros, E., Salas-Salvadó, J., Covas, M.-I., Corella, D., Arós, F., Gómez-Gracia, E., Ruiz-Gutiérrez, V., Fiol, M., Lapetra, J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1200303 · Cited by 4,257 · see citing works
Self-citationRetractedEstruch, R., Ros, E., Salas-Salvadó, J., Covas, M.-I., Corella, D., Arós, F., Gómez-Gracia, E., Ruiz-Gutiérrez, V., Fiol, M., Lapetra, J., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmc1806491 · Cited by 1,008 · see citing works
Self-citationRetractedA new generation of Ca2+ indicators with greatly improved fluorescence properties.
Grynkiewicz, G., Poenie, M., & Tsien, R. Y. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)83641-4 · Cited by 21,722 · see citing works
A novel potent vasoconstrictor peptide produced by vascular endothelial cells
Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y. I., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K., & Masaki, T. (1988) · Nature · doi:10.1038/332411a0 · Cited by 10,716 · see citing works
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023 · see citing works
Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
Ignarro, L. J., Buga, G. M., Wood, K. S., Byrns, R. E., & Chaudhuri, G. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.24.9265 · Cited by 5,074 · see citing works
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., & Zeiher, A. M. (1999) · Nature · doi:10.1038/21224 · Cited by 3,591 · see citing works
A synthetic inhibitor of the mitogen-activated protein kinase cascade.
Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., & Saltiel, A. R. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.17.7686 · Cited by 2,679 · see citing works
Schächinger, V., Britten, M. B., & Zeiher, A. M. (2000) · Circulation · doi:10.1161/01.cir.101.16.1899 · Cited by 2,584 · see citing works
Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer
Kris‐Etherton, P. M., Hecker, K. D., Bonanome, A., Coval, S. M., Binkoski, A. E., Hilpert, K. F., Griel, A. E., & Etherton, T. D. (2002) · The American Journal of Medicine · doi:10.1016/s0002-9343(01)00995-0 · Cited by 2,544 · see citing works
Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations
Kalyanaraman, B., Darley-Usmar, V. M., Davies, K. J. A., Dennery, P. A., Forman, H. J., Grisham, M. B., Mann, G. E., Moore, K. P., Roberts, L. J., & Ischiropoulos, H. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.09.030 · Cited by 1,795 · see citing works
THE DIET AND 15-YEAR DEATH RATE IN THE SEVEN COUNTRIES STUDY
KEYS, A., MIENOTTI, A., KARVONEN, M. J., ARAVANIS, C., BLACKBURN, H., BUZINA, R., DJORDJEVIC, B. S., DONTAS, A. S., FIDANZA, F., KEYS, M. H., et al. (1986) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a114480 · Cited by 1,790 · see citing works
Effects of a Mediterranean-Style Diet on Cardiovascular Risk Factors: A Randomized Trial
Estruch, R., Martínez-González, M. Á., Corella, D., Salas-Salvadó, J., Ruiz-Gutiérrez, V., Covas, M. I., Fiol, M., Gómez-Gracia, E., López-Sabater, M. C., Vinyoles, E., et al. (2006) · Annals of Internal Medicine · doi:10.7326/0003-4819-145-1-200607040-00004 · Cited by 1,704 · see citing works
Du, X. L., Edelstein, D., Dimmeler, S., Ju, Q., Sui, C., & Brownlee, M. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11235 · Cited by 907 · see citing works
Wardman, P. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.06.026 · Cited by 863 · see citing works
Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant
Heumüller, S., Wind, S., Barbosa-Sicard, E., Schmidt, H. H. H. W., Busse, R., Schröder, K., & Brandes, R. P. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.100214 · Cited by 735 · see citing works
Wymann, M. P., Bulgarelli-Leva, G., Zvelebil, M., Pirola, L., Vanhaesebroeck, B., Waterfield, M. D., & Panayotou, G. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.4.1722 · Cited by 684 · see citing works
Molecular mechanisms underlying the activation of eNOS
Fleming, I. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0767-7 · Cited by 437 · see citing works
Endothelial Function Predicts Future Development of Coronary Artery Disease
Bugiardini, R., Manfrini, O., Pizzi, C., Fontana, F., & Morgagni, G. (2004) · Circulation · doi:10.1161/01.cir.0000128208.22378.e3 · Cited by 350 · see citing works
Du, X., Edelstein, D., Obici, S., Higham, N., Zou, M., & Brownlee, M. (2006) · Journal of Clinical Investigation · doi:10.1172/jci23354 · Cited by 344 · see citing works
Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKKβ
Kim, F., Tysseling, K. A., Rice, J., Pham, M., Haji, L., Gallis, B. M., Baas, A. S., Paramsothy, P., Giachelli, C. M., Corson, M. A., et al. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000160549.60980.a8 · Cited by 307 · see citing works
Lüscher, T. F., Yang, Z., Tschudi, M. R., et al. (1990) · Circulation Research · doi:10.1161/01.res.66.4.1088 · Cited by 296 · see citing works
Toledo, E., Hu, F. B., Estruch, R., Buil-Cosiales, P., Corella, D., Salas-Salvadó, J., Covas, M. I., Arós, F., Gómez-Gracia, E., Fiol, M., et al. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-207 · Cited by 289 · see citing works
Tresserra‐Rimbau, A., Medina‐Remón, A., Pérez‐Jiménez, J., Martínez‐González, M. Á., Covas, M.-I., Corella, D., Salas‐Salvadó, J., Gómez‐Gracia, E., Lapetra, J., Arós, F., et al. (2013) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2012.10.008 · Cited by 268 · see citing works
Self-citationIncreased Activity of Endogenous Endothelin in Patients With Type II Diabetes Mellitus
Cardillo, C., Campia, U., Bryant, M. B., & Panza, J. A. (2002) · Circulation · doi:10.1161/01.cir.0000032260.01569.64 · Cited by 258 · see citing works
Frantz, B., Klatt, T., Pang, M., Parsons, J. N., Rolando, A. M., Williams, H. R., Tocci, M. J., O'Keef, S. J., & O’Neill, E. A. (1998) · Biochemistry · doi:10.1021/bi980832y · Cited by 200 · see citing works
NADPH oxidase activity is required for endothelial cell proliferation and migration
Abid, M. R., Kachra, Z., Spokes, K., & Aird, W. C. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)02305-x · Cited by 191 · see citing works
Medina‐Remón, A., Barrionuevo‐Gonzalez, A., Zamora‐Ros, R., Andrés‐Lacueva, C., Estruch, R., Martínez‐González, M. Á., Díez‐Espino, J., & Lamuela-Raventós, R. M. (2008) · Analytica Chimica Acta · doi:10.1016/j.aca.2008.12.012 · Cited by 188 · see citing works
Brown, J. A., Reading, S. J., Jones, S., Fitchett, C., Howl, J., Martin, A. Y., Longland, C. L., Michelangeli, F., Dubrova, Y. E., & Brown, C. A. (2000) · Laboratory Investigation · doi:10.1038/labinvest.3780006 · Cited by 182 · see citing works
Patel, H., Chen, J., Das, K. C., & Kavdia, M. (2013) · Cardiovascular Diabetology · doi:10.1186/1475-2840-12-142 · Cited by 179 · see citing works
Atochin, D. N., Wang, A. R., Liu, V. W. T., Critchlow, J. D., Dantas, A. P., Looft‐Wilson, R. C., Murata, T., Salomone, S., Shin, H. K., Ayata, C., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29877 · Cited by 168 · see citing works
Martin, S., Andriambeloson, E., Takeda, K., & Andriantsitohaina, R. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704603 · Cited by 150 · see citing works
Activation of Endothelial Nitric-oxide Synthase by the p38 MAPK in Response to Black Tea Polyphenols
Anter, E., Thomas, S. R., Schulz, E., Shapira, O. M., Vita, J. A., & Keaney, J. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405547200 · Cited by 142 · see citing works
Endothelial dysfunction in diabetes: multiple targets for treatment
Ding, H., & Triggle, C. R. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-010-0807-3 · Cited by 98 · see citing works
Nicholson, S. K., Tucker, G. A., & Brameld, J. M. (2009) · British Journal Of Nutrition · doi:10.1017/s0007114509993485 · Cited by 90 · see citing works
Inhibition of Cyclic Strain-Induced Endothelin-1 Gene Expression by Resveratrol
Liu, J., Chen, J., Chan, P., Cheng, C., & Cheng, T. (2003) · Hypertension · doi:10.1161/01.hyp.0000103162.76220.51 · Cited by 89 · see citing works
Liu, S., Ma, X., GONG, M., Shi, L., Lincoln, T., & Wang, S. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.12.025 · Cited by 80 · see citing works
Total polyphenol excretion and blood pressure in subjects at high cardiovascular risk
Medina-Remón, A., Zamora-Ros, R., Rotchés-Ribalta, M., Andres-Lacueva, C., Martínez-González, M. A., Covas, M. I., Corella, D., Salas-Salvadó, J., Gómez-Gracia, E., Ruiz-Gutiérrez, V., et al. (2011) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2009.10.019 · Cited by 80 · cited 1× · see citing works
“All blots were developed using an enhanced chemiluminescence kit (Supersignal West Dura Extended Duration Substrate) from Pierce (Rockford, IL, USA).”
MethodAnter, E., Chen, K., Shapira, O. M., Karas, R. H., & Keaney, J. F. (2005) · Circulation Research · doi:10.1161/01.res.0000168807.63013.56 · Cited by 78 · see citing works
Weinbrenner, T., Fitó, M., Farré, M., Sáez, G. T., Rijken, P. J., Tormos, C., Coolen, S. A. J., de la Torre, R., & Covas, M. I. (2004) · PubMed · Cited by 76 · see citing works
Changing the Mediterranean Diet: Effects on Blood Pressure
Strazzullo, P., Ferro-Luzzi, A., Siani, A., Scaccini, C., Sette, S., Catasta, G., & Mancini, M. (1986) · Journal of Hypertension · doi:10.1097/00004872-198608000-00003 · Cited by 75 · see citing works
Insulin resistance, lipotoxicity and endothelial dysfunction
Imrie, H., Abbas, A., & Kearney, M. T. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.09.025 · Cited by 74 · see citing works
Rodríguez-Lagunas, M. J., Martín-Venegas, R., Moreno, J. J., et al. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00397.2009 · Cited by 72 · see citing works
Self-citationSerizawa, K., Yogo, K., Aizawa, K., Tashiro, Y., & Ishizuka, N. (2011) · Cardiovascular Diabetology · doi:10.1186/1475-2840-10-105 · Cited by 64 · see citing works
Wong, W. T., Tian, X. Y., Xu, A., Ng, C., Lee, H. K., Chen, Z., Au, C. L., Yao, X., & Huang, Y. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2831 · Cited by 62 · see citing works
Monti, L. D., Landoni, C., Setola, E., Galluccio, E., Lucotti, P., Sandoli, E. P., Origgi, A., Lucignani, G., Piatti, P., & Fazio, F. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00629.2003 · Cited by 52 · see citing works
Wallis, M. G., Smith, M. E., Kolka, C. M., Zhang, L., Richards, S. M., Rattigan, S., & Clark, M. G. (2005) · Diabetologia · doi:10.1007/s00125-005-1887-z · Cited by 38 · see citing works
Kopf, T., & Schmitz, G. (2013) · Journal of Chromatography B · doi:10.1016/j.jchromb.2013.08.016 · Cited by 33 · see citing works
Unsaturated free fatty acids inhibit Ca2+ mobilization and NO release in endothelial cells.
Kuroda, R., Hirata, K., Kawashima, S., & Yokoyama, M. (2001) · PubMed · Cited by 22 · see citing works
Moreno, J. J. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38830-5 · Cited by 18 · see citing works
Self-citationVouyouka, A. G., Jiang, Y., Rastogi, R., & Basson, M. D. (2006) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2006.06.033 · Cited by 14 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [20]Rodríguez-Lagunas M.J. Martín-Venegas R. Moreno J.J. Ferrer R. PGE2 promotes Ca2+-mediated epithelial barrier disruption through EP1 and EP4 receptors in Caco-2 cell monolayers American Journal of Physiology. Cell Physiology 299 2010 C324 C334 20484658 20484658
Cited by
Sorted by citations
Dinu, M., Pagliai, G., Casini, A., & Sofi, F. (2018) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2017.58 · Cited by 1,016 · see citing works
Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases
Mirabelli, M., Chiefari, E., Arcidiacono, B., Corigliano, D. M., Brunetti, F. S., Maggisano, V., Russo, D., Foti, D. P., & Brunetti, A. (2020) · Nutrients · doi:10.3390/nu12041066 · Cited by 272 · see citing works
“The anti-hypertensive actions of EVOO, and EVOO-related functional compounds, appear to be related to an increased endothelial synthesis of nitric oxide (NO), a potent vasodilator [198,199], which is disrupted in carriers of Glu298Asp polymorphism in the endothelial NO synthase (eNOS) gene [200] as well as under IR co…”
BackgroundInfluentialGaforio, J. J., Visioli, F., Alarcón-de-la-Lastra, C., Castañer, O., Delgado-Rodríguez, M., Fitó, M., Hernández, A. F., Huertas, J. R., Martínez-González, M. A., Menendez, J. A., et al. (2019) · Nutrients · doi:10.3390/nu11092039 · Cited by 187 · see citing works
Henríquez, G., Gomez, A., Guerrero, E., & Narayan, M. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00381 · Cited by 83 · see citing works
Sanchez-Rodriguez, E., Lima-Cabello, E., Biel-Glesson, S., Fernandez-Navarro, J. R., Calleja, M. A., Roca, M., Espejo-Calvo, J. A., Gil-Extremera, B., Soria-Florido, M., De la Torre, R., et al. (2018) · Nutrients · doi:10.3390/nu10050626 · Cited by 59 · see citing works
- Authors
- Storniolo, C. E., Roselló-Catafau, J., Pintó, X., Mitjavila, M. T., & Moreno, J. J.
- Affiliations
- Universitat de Barcelona (ES)
- Bellvitge University Hospital (ES)
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2014
- Volume
- 2
- Pages
- 971-977
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC4215463
- OpenAlex
- W2046300274
- Cited by
- 121
- References
- 51
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 7 · 2021: 11 · 2020: 14 · 2019: 17 · 2018: 14 · 2017: 7 · 2016: 7 · 2015: 11
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Spanish Ministry of Health (RD06/0045)
- Fondo Europeo de Desarrollo Regional
- Spanish Ministry of Science (BFU2007-61727/BFI)
- Generalitat de Catalunya (2009SGR00438)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Organic Chemistry › Edible Oils Quality and Analysis
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Keywords
- extra virgin olive oil, polyphenols, endothelial dysfunction, nitric oxide, endothelin-1, type 2 diabetes, hyperglycemia, free fatty acids, linoleic acid, oleic acid, hydroxytyrosol, reactive oxygen species, intracellular calcium, acetylcholine, cardioprotection
- MeSH terms
- Olive Oil, Cell Line, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Glucose, Nitric Oxide, Oleic Acid, Endothelin-1, Linoleic Acid, Endothelial Cells, Nitric Oxide Synthase Type III, Polyphenols
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review