Entry #: 28
Date: 12 December 2017
Section: Vascular biology
Topic: Mediterranean polyphenols and endothelial cells
Type: Original article

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Expert review of literature related to olives and olive oil

D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis


Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: A potentially protective mechanism in atherosclerotic vascular disease and cancer


Scoditti et al

Citation / Year

(1) / 2012


Oleuropein, hydroxytyrosol, resveratrol, quercetin, vascular endothelial cells, angiogenesis, matrix metalloproteinase, cyclooxygenase


The Mediterranean diet has been associated with a decrease of numerous diseases which are linked to inflammation and oxidative stress including cardiovascular and metabolic diseases, neurodegeneration and cancer (2-8). The current paradigm indicates that the high antioxidant polyphenols which form part of the Mediterranean diet are largely responsible for the beneficial for the health effects (9-12). Major phenolics from virgin olive oil (including oleuropein and hydroxytyrosol) (13, 14), and from red wine (resveratrol and quercetin) (15-18), have been shown to possess potent antioxidant and anti-inflammatory effects. In this study, the effects of these major dietary polyphenols on endothelial cell inflammation and angiogenesis was investigated. In particular, the regulation of oleuropein, hydroxytyrosol, resveratrol and quercetin on the regulation of the key inflammatory response associated cyclooxygenase-2 enzyme (COX-2) and matrix metalloproteinase-9 (MMP-9) linked to angiogenesis was investigated.

Key points and implications

Human umbilical vein endothelial cells (and human microvascular endothelial-1 cells, for selected control experiments), were used in this study. Cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and treated with or without 0.1-50 μM polyphenols. Conventional matrigel tube formation and scratch migration assays were performed and to elucidate molecular mechanisms of action, immunoblotting and immunocytochemistry experiments were conducted. Firstly, it is important to note that treatment of cells with up to 50 μM of the polyphenols for 24 hours did not produce any signs of cytotoxicity. The key findings indicated that oleuropein, hydroxytyrosol, resveratrol and quercetin: 1) inhibit angiogenic responses in PMA-stimulated endothelial cells as assessed by scratch migration and tube formation experiments, 2) inhibit MMP-9 activity and expression in PMA-stimulated endothelial cells, 3) inhibit PMA-induced COX-2 activity and expression, and 4) reduce PMA-mediated levels of reactive oxygen species and nuclear factor (NF)-B. In summary these findings highlight that the dietary polyphenols produce anti-inflammatory and anti-angiogenic effects in stimulated endothelial cells via the reactive oxygen species-mediated NF-B pathway resulting in the modulation of the expression of MMP-9 and COX-2. In general, these basic in vitro studies are important for delineating the molecular mechanisms of action accounting the beneficial health effects of polyphenol-rich diets such as the Mediterranean diet.

Related publications

  1. E. Scoditti et al., Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer. Archives of biochemistry and biophysics 527, 81-89 (2012).
  2. C. Assaf-Balut et al., A Mediterranean diet with additional extra virgin olive oil and pistachios reduces the incidence of gestational diabetes mellitus (GDM): A randomized controlled trial: The St. Carlos GDM prevention study. PloS one 12, e0185873 (2017).
  3. M. Bonaccio, L. Iacoviello, G. de Gaetano, I. Moli-Sani, The Mediterranean diet: the reasons for a success. Thrombosis research 129, 401-404 (2012).
  4. R. Estruch et al., Primary prevention of cardiovascular disease with a Mediterranean diet. The New England journal of medicine 368, 1279-1290 (2013).
  5. A. R. Khalatbary, Olive oil phenols and neuroprotection. Nutritional neuroscience 16, 243-249 (2013).
  6. L. Parkinson, S. Cicerale, The Health Benefiting Mechanisms of Virgin Olive Oil Phenolic Compounds. Molecules 21, (2016).
  7. P. Viola, M. Viola, Virgin olive oil as a fundamental nutritional component and skin protector. Clinics in dermatology 27, 159-165 (2009).
  8. W. C. Willett, The Mediterranean diet: science and practice. Public health nutrition 9, 105-110 (2006).
  9. H. Shamshoum, F. Vlavcheski, E. Tsiani, Anticancer effects of oleuropein. BioFactors 43, 517-528 (2017).
  10. M. N. Vissers, P. L. Zock, M. B. Katan, Bioavailability and antioxidant effects of olive oil phenols in humans: a review. European journal of clinical nutrition 58, 955-965 (2004).
  11. M. N. Vissers, P. L. Zock, A. J. Roodenburg, R. Leenen, M. B. Katan, Olive oil phenols are absorbed in humans. The Journal of nutrition 132, 409-417 (2002).
  12. H. Zrelli, M. Kusunoki, H. Miyazaki, Role of Hydroxytyrosol-dependent Regulation of HO-1 Expression in Promoting Wound Healing of Vascular Endothelial Cells via Nrf2 De Novo Synthesis and Stabilization. Phytotherapy research : PTR 29, 1011-1018 (2015).
  13. S. H. Omar, Oleuropein in olive and its pharmacological effects. Scientia pharmaceutica 78, 133-154 (2010).
  14. A. Parzonko, M. E. Czerwinska, A. K. Kiss, M. Naruszewicz, Oleuropein and oleacein may restore biological functions of endothelial progenitor cells impaired by angiotensin II via activation of Nrf2/heme oxygenase-1 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 20, 1088-1094 (2013).
  15. X. Vitrac et al., Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life sciences 72, 2219-2233 (2003).
  16. T. Walle, Bioavailability of resveratrol. Annals of the New York Academy of Sciences 1215, 9-15 (2011).
  17. M. Aviram, B. Fuhrman, Wine flavonoids protect against LDL oxidation and atherosclerosis. Annals of the New York Academy of Sciences 957, 146-161 (2002).
  18. Y. B. Shaik et al., Role of quercetin (a natural herbal compound) in allergy and inflammation. Journal of biological regulators and homeostatic agents 20, 47-52 (2006).