Skip to main content
SpringerLink
Log in

Coumaric Acid Induces Mitochondrial Damage and Oxidative-Mediated Cell Death of Human Endothelial Cells

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Evidence that higher natural antioxidants (NA) intake provides cardiovascular protection is contradictory. The endothelium plays a pivotal role in cardiovascular homeostasis, and for this reason, the molecular events resulting from the interaction of NA with endothelial cells (ECs) are actively investigated. Here, we show that moderately high doses of coumaric acid (CA) induced intracellular reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ECs death. Treatment of ECs with cyclosporine A, a mitochondrial permeability transition pore inhibitor, prevented the oxidative-mediated cell damage indicating mitochondrial involvement in CA-induced ECs impairment. CA-induced intracellular ROS generation was counteracted by the specific cytochrome P450 (CYP) 2C9 inhibitor sulfaphenazole (SPZ). SPZ also prevented CA-induced mitochondrial membrane depolarization and ECs death, implicating CYP2C9 in mediating the cellular response upon CA treatment. Our results indicate that moderately high doses of CA can promote CYP2C9-mediated oxidative stress eliciting mitochondrial-dependent ECs death and may pave the way toward mechanistic insight into NA effects on cardiovascular cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Cai, H., & Harrison, D. G. (2000). Endothelial dysfunction in cardiovascular diseases—The role of oxidant stress. Circulation Research, 87, 840–844.

    Article  PubMed  CAS  Google Scholar 

  2. Willcox, B. J., Curb, J. D., & Rodriguez, B. L. (2008). Antioxidants in cardiovascular health and disease: Key lessons from epidemiologic studies. American Journal of Cardiology, 101, 75D–86D.

    Article  PubMed  CAS  Google Scholar 

  3. Kaliora, A. C., Dedoussis, G. V., & Schmidt, H. (2006). Dietary antioxidants in preventing atherogenesis. Atherosclerosis, 187, 1–17.

    Article  PubMed  CAS  Google Scholar 

  4. Irani, K. (2000). Oxidant signaling in vascular cell growth, death, and survival: A review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circulation Research, 87, 179–183.

    Article  PubMed  CAS  Google Scholar 

  5. Galati, G., Sabzevari, O., Wilson, J. X., & O’Brien, P. J. (2002). Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicology, 177, 91–104.

    Article  PubMed  CAS  Google Scholar 

  6. Schonthal, A. H. (2011). Adverse effects of concentrated green tea extracts. Molecular Nutrition & Food Research, 55, 874–885.

    Article  Google Scholar 

  7. Stevenson, D. E., & Hurst, R. D. (2007). Polyphenolic phytochemicals—Just antioxidants or much more? Cellular and Molecular Life Sciences, 64, 2900–2916.

    Article  PubMed  CAS  Google Scholar 

  8. Yen, G. C., Duh, P. D., Tsai, H. L., & Huang, S. L. (2003). Pro-oxidative properties of flavonoids in human lymphocytes. Bioscience, Biotechnology, and Biochemistry, 67, 1215–1222.

    Article  PubMed  CAS  Google Scholar 

  9. Zinellu, A., Sotgia, S., Scanu, B., Pintus, G., Posadino, A. M., Cossu, A., et al. (2009). S-homocysteinylated LDL apolipoprotein B adversely affects human endothelial cells in vitro. Atherosclerosis, 206, 40–46.

    Article  PubMed  CAS  Google Scholar 

  10. Zhao, R., Fang, S. H., Lin, K. N., Huang, X. Q., Lu, Y. B., Zhang, W. P., et al. (2011). Pranlukast attenuates hydrogen peroxide-induced necrosis in endothelial cells by inhibiting oxygen reactive species-mediated collapse of mitochondrial membrane potential. Journal of Cardiovascular Pharmacology, 57, 479–488.

    Article  PubMed  CAS  Google Scholar 

  11. Viswanathan, S., Hammock, B. D., Newman, J. W., Meerarani, P., Toborek, M., & Hennig, B. (2003). Involvement of CYP2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells. Journal of the American College of Nutrition, 22, 502–510.

    Article  PubMed  CAS  Google Scholar 

  12. Posadino, A. M., Porcu, M. C., Marongiu, B., Cossu, A., Piras, A., Porcedda, S., et al. (2012). Antioxidant activity of supercritical carbon dioxide extracts of Salvia desoleana on two human endothelial cell models. Food Research International, 46, 354–359.

    Article  Google Scholar 

  13. Pasciu, V., Posadino, A. M., Cossu, A., Sanna, B., Tadolini, B., Gaspa, L., et al. (2010). Akt downregulation by Flavin oxidase-induced ROS generation mediates dose-dependent endothelial cell damage elicited by natural antioxidants. Toxicological Sciences, 114, 101–112.

    Article  PubMed  CAS  Google Scholar 

  14. Fleming, I. (2001). Cytochrome P450 enzymes in vascular homeostasis. Circulation Research, 89, 753–762.

    Article  PubMed  CAS  Google Scholar 

  15. Cossu, A., Posadino, A. M., Giordo, R., Emanueli, C., Sanguinetti, A. M., Piscopo, A., et al. (2012). Apricot melanoidins prevent oxidative endothelial cell death by counteracting mitochondrial oxidation and membrane depolarization. PLoS ONE, 7, e48817.

    Article  PubMed  CAS  Google Scholar 

  16. Salvioli, S., Ardizzoni, A., Franceschi, C., & Cossarizza, A. (1997). JC-1, but not DiOC(6)(3) or rhodamine 123, is a reliable fluorescent probe to assess Delta Psi changes in intact cells: Implications for studies on mitochondrial functionality during apoptosis. FEBS Letters, 411, 77–82.

    Article  PubMed  CAS  Google Scholar 

  17. Klinge, C. M., Wickramasinghe, N. S., Ivanova, M. M., & Dougherty, S. M. (2008). Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J, 22, 2185–2197.

    Article  PubMed  CAS  Google Scholar 

  18. Schaefer, S., Baum, M., Eisenbrand, G., Dietrich, H., Will, F., & Janzowski, C. (2006). Polyphenolic apple juice extracts and their major constituents reduce oxidative damage in human colon cell lines. Molecular Nutrition & Food Research, 50, 24–33.

    Article  CAS  Google Scholar 

  19. Cao, G., Sofic, E., & Prior, R. L. (1997). Antioxidant and prooxidant behavior of flavonoids: Structure-activity relationships. Free Radical Biology & Medicine, 22, 749–760.

    Article  CAS  Google Scholar 

  20. Gadacha, W., Ben-Attia, M., Bonnefont-Rousselot, D., Aouani, E., Ghanem-Boughanmi, N., & Touitou, Y. (2009). Resveratrol opposite effects on rat tissue lipoperoxidation: Pro-oxidant during day-time and antioxidant at night. Redox Report, 14, 154–158.

    Article  PubMed  CAS  Google Scholar 

  21. Orrenius, S., Gogvadze, A., & Zhivotovsky, B. (2007). Mitochondrial oxidative stress: Implications for cell death. Annual Reviews Pharmacology, 47, 143–183.

    Article  CAS  Google Scholar 

  22. Puntarulo, S., & Cederbaum, A. I. (1998). Production of reactive oxygen species by microsomes enriched in specific human cytochrome P450 enzymes. Free Radical Biology & Medicine, 24, 1324–1330.

    Article  CAS  Google Scholar 

  23. Guengerich, F. P. (2008). Cytochrome P450 and chemical toxicology. Chemical Research in Toxicology, 21, 70–83.

    Article  PubMed  CAS  Google Scholar 

  24. Fleming, I., Michaelis, U. R., Bredenkotter, D., Fisslthaler, B., Dehghani, F., Brandes, R. P., et al. (2001). Endothelium-derived hyperpolarizing factor synthase (cytochrome P4502C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circulation Research, 88, 44–51.

    Article  PubMed  CAS  Google Scholar 

  25. Lefevre, J., Michaud, S. E., Haddad, P., Dussault, S., Menard, C., Groleau, J., et al. (2007). Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: Effect on endothelial progenitor cells and nitric oxide. The FASEB Journal, 21, 3845–3852.

    Article  CAS  Google Scholar 

  26. Carru, C., Pasciu, V., Sotgia, S., Zinellu, A., Nicoli, M. C., Deiana, L., et al. (2011). The oxidative state of LDL is the major determinant of anti/prooxidant effect of coffee on Cu2 + catalysed peroxidation. The Open Biochemistry Journal, 5, 1.

    Article  PubMed  CAS  Google Scholar 

  27. Sale, S., Verschoyle, R. D., Boocock, D., Jones, D. J., Wilsher, N., Ruparelia, K. C., et al. (2004). Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene. British Journal of Cancer, 90, 736–744.

    Article  PubMed  CAS  Google Scholar 

  28. Bottner, M., Christoffel, J., Jarry, H., & Wuttke, W. (2006). Effects of long-term treatment with resveratrol and subcutaneous and oral estradiol administration on pituitary function in rats. Journal of Endocrinology, 189, 77–88.

    Article  PubMed  Google Scholar 

  29. Lambert, J. D., Kennett, M. J., Sang, S., Reuhl, K. R., Ju, J., & Yang, C. S. (2010). Hepatotoxicity of high oral dose (−)-epigallocatechin-3-gallate in mice. Food and Chemical Toxicology, 48, 409–416.

    Article  PubMed  CAS  Google Scholar 

  30. Vitrac, X., Desmouliere, A., Brouillaud, B., Krisa, S., Deffieux, G., Barthe, N., et al. (2003). Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sciences, 72, 2219–2233.

    Article  PubMed  CAS  Google Scholar 

  31. Bertelli, A. A. E., Giovannini, L., Stradi, R., Bertelli, A., & Tillement, J. P. (1996). Plasma, urine and tissue levels of trans- and cis-resveratrol (3,4′,5-trihydroxystilbene) after short-term or prolonged administration of red wine to rats. International Journal of Tissue Reactions, 18, 67–71.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work funded by the Italian Ministry of University (PRIN 08), Banco di Sardegna Foundation and Sardinia Region L.R. n7 2007.

Conflict of interest

  The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Sassari, Viale San Pietro 34/B, 07100, Sassari, Italy

    Anna Maria Posadino, Annalisa Cossu, Roberta Giordo, Angelo Zinellu, Salvatore Sotgia, Antonella Vardeu, Phu Thi Hoa, Luca Deiana, Ciriaco Carru & Gianfranco Pintus

  2. Laboratory of Vascular Biology, University of Sassari, Viale San Pietro 34/B, 07100, Sassari, Italy

    Anna Maria Posadino, Annalisa Cossu, Roberta Giordo, Antonella Vardeu, Phu Thi Hoa & Gianfranco Pintus

  3. Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari, Sassari, Italy

    Ciriaco Carru & Gianfranco Pintus

  4. Department of Biochemistry, Huè University of Medicine and Pharmacy, Hue, Vietnam

    Phu Thi Hoa

Authors
  1. Anna Maria Posadino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annalisa Cossu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberta Giordo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angelo Zinellu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Salvatore Sotgia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonella Vardeu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Phu Thi Hoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luca Deiana
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ciriaco Carru
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gianfranco Pintus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gianfranco Pintus.

Additional information

Anna Maria Posadino and Annalisa Cossu: equal contribution.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Posadino, A.M., Cossu, A., Giordo, R. et al. Coumaric Acid Induces Mitochondrial Damage and Oxidative-Mediated Cell Death of Human Endothelial Cells. Cardiovasc Toxicol 13, 301–306 (2013). https://doi.org/10.1007/s12012-013-9205-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-013-9205-3

Keywords

Search

Navigation