Skip to main content
SpringerLink
Log in

Mechanistic Clues in the Protective Effect of Ellagic Acid Against Apoptosis and Decreased Mitochondrial Respiratory Enzyme Activities in Myocardial Infarcted Rats

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Our previous study described the cardioprotective effects of ellagic acid in an isoproterenol-induced myocardial infarction model. In this study, we are reporting the mechanism of protective action of ellagic acid with respect to apoptosis and mitochondrial respiratory enzymes. Ellagic acid (7.5 and 15 mg/kg) was administered orally as a pretreatment for 10 days. Then, isoproterenol (100 mg/kg) was injected subcutaneously to rats at an interval of 24 h for 2 days. Myocardial infarction was quantified by planimetry. Apoptosis was measured by apoptotic gene expressions. The levels of mitochondrial respiratory enzymes were also measured. Isoproterenol-induced myocardial infarcted rats showed increased infarct size, a decrease in myocardial expression of the Bcl-2 gene and an increase in myocardial expression of the BAX gene. Fas ligand and caspases were markedly elevated along with compromised respiratory marker enzymes in isoproterenol-induced rats. Ellagic acid pretreatment reduced the infarct size, regulated apoptotic gene expressions and enhanced the activities of mitochondrial respiratory marker enzymes and cell viability, thereby protecting the myocardium against isoproterenol-induced myocardial infarction. The decreased infarct size associated with inhibited apoptosis and increased respiratory marker enzymes provide insight on the role of ellagic acid in antiapoptotic mechanism, and it may be the reason for its cardioprotective activity.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Sparagna, G. C., Chicco, A. J., Murphy, R. C., Bristow, M. R., Johnson, C. A., Rees, M. L., et al. (2007). Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure. Journal of Lipid Research, 48, 1559–1570.

    Article  PubMed  CAS  Google Scholar 

  2. Krijnen, P. A., Nijmeijer, R., Meijer, C. J., Visser, C. A., Hack, C. E., & Niessen, H. W. (2002). Apoptosis in myocardial ischaemia and infarction. Journal of Clinical Pathology, 55, 801–811.

    Article  PubMed  CAS  Google Scholar 

  3. Hare, J. M. (2001). Oxidative stress and apoptosis in heart failure progression. Circulation Research, 89, 198–200.

    PubMed  CAS  Google Scholar 

  4. Huang, J., Ito, Y., Morikawa, M., Kobune, M., Sasaki, K., Abe, T., et al. (2003). Bcl-xL gene transfer protects the heart against ischemia/reperfusion injury. Biochemical and Biophysical Research and Communications, 311, 64–70.

    Article  CAS  Google Scholar 

  5. Vatner, D. E., Asai, K., Iwase, M., Ishikawa, Y., Shannon, R. P., Homcy, C. J., et al. (1999). Beta-adrenergic receptor-G protein-adenylyl cyclase signal transduction in the failing heart. American Journal of Cardiology, 83, 80H–85H.

    Article  PubMed  CAS  Google Scholar 

  6. Kukin, M. L., Kalman, J., Charney, R. H., Levy, D. K., Buchholz-Varley, C., Ocampo, O. N., et al. (1999). Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation, 99, 2645–2651.

    PubMed  CAS  Google Scholar 

  7. Nirmala, C., & Puvanakrishnan, R. (1996). Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Molecular and Cellular Biochemistry, 159, 85–93.

    Article  PubMed  CAS  Google Scholar 

  8. Yüce, A., Ateşşahin, A., Çeribaşı, A. O., & Aksakal, M. (2007). Ellagic acid prevents cisplatin induced oxidative stress in liver and heart tissue of rats. Basic & Clinical Pharmacology & Toxicology, 101, 345–349.

    Article  Google Scholar 

  9. Türk, G., Ateşşahin, A., Sönmez, M., Çeribaşı, A. O., & Yüce, A. (2008). Improvement of cisplatin induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertility and Sterility, 89, 1474–1481.

    Article  PubMed  Google Scholar 

  10. Aggarwal, B. B., & Shishoida, S. (2006). Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical Pharmacology, 71, 1397–1421.

    Article  PubMed  CAS  Google Scholar 

  11. Mari Kannan, M., & Darlin Quine, S. (2011). Ellagic acid ameliorates isoproterenol induced oxidative stress: evidences from electrocardiological, biochemical and histological studies. European Journal of Pharmacology, 659, 45–52.

    Article  Google Scholar 

  12. Punithavathi, V. R., & Prince, P. S. M. (2010). Pretreatment with a combination of quercetin and alpha-tocopherol ameliorates adenosine triphosphatases and lysosomal enzymes in myocardial infarcted rats. Life Sciences, 86, 178–184.

    Article  PubMed  CAS  Google Scholar 

  13. Ojha, N., Roy, S., Radtke, J., Simonetti, O., Gnyawali, S., Zweier, J. L., et al. (2008). Characterization of the structural and functional changes in the myocardium following focal ischemia–reperfusion injury. American Journal of Physiology. Heart and Circulatory Physiology, 294, H2435–H2443.

    Article  PubMed  CAS  Google Scholar 

  14. Takasawa, M., Hayakawa, M., Sugiyama, S., Hattori, K., Ito, T., & Ozawa, T. (1993). Age-associated damage in mitochondrial function in rat hearts. Experimental Gerontology, 28, 269–280.

    Article  PubMed  CAS  Google Scholar 

  15. Minakami, S., Ringler, R. L., & Singer, T. P. (1962). Studies on the respiratory chain-linked dihydrodiphosphopyridine nucleotide dehydrogenase: assay of the enzyme in particulate and in soluble preparations. The Journal of Biological Chemistry, 237, 569–576.

    PubMed  CAS  Google Scholar 

  16. Pearl, W., Cascarano, J., & Zweifach, B. W. (1963). Microdetermination of cytochrome oxidase in rat tissues by oxidation on N-phenyl-p-phenylene diamine or ascorbic acid. The Journal of Histochemistry and Cytochemistry, 11, 102–104.

    Article  CAS  Google Scholar 

  17. Kato, F., Tanaka, M., & Nakamura, K. (1999). Rapid fluorometric assay for cell viability and cell growth using nucleic acid staining and cell lysis agents. Toxicology in Vitro, 13, 923–929.

    Article  PubMed  CAS  Google Scholar 

  18. Strober, W. (1997). Trypan blue exclusion test of cell viability, in Current protocols in immunology (Coico, R., ed) (pp. A.3B.1–A.3B). Wiley, London.

  19. Baks, T., van Geuns, R. J., Biagini, E., Wielopolski, P., Mollet, N. R., Cademartiri, F., et al. (2005). Recovery of left ventricular function after primary angioplasty for acute myocardial infarction. European Heart Journal, 26, 1070–1077.

    Article  PubMed  Google Scholar 

  20. Miura, T., & Miki, T. (2008). Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Research in Cardiology, 103, 501–513.

    Article  PubMed  Google Scholar 

  21. Altman, F. P. (1976). Tetrazolium salts and formazans. Progress in Histochemistry and Cytochemistry, 9, 1–56.

    PubMed  CAS  Google Scholar 

  22. Nachlas, M. M., & Shnitka, T. K. (1963). Macroscopic identification of early myocardial infarcts by alterations in dehydrogenase activity. The American Journal of Pathology, 42, 379–405.

    PubMed  CAS  Google Scholar 

  23. Ramkissoon, R. A. (1966). Macroscopic identification of early myocardial infarction by dehydrogenase alterations. Journal of Clinical Pathology, 19, 479–481.

    Article  PubMed  CAS  Google Scholar 

  24. Stanely Mainzen Prince, P., & Priya, S. (2010). Preventive effects of rutin on lysosomal enzymes in isoproterenol induced cardio toxic rats: biochemical, histological and in vitro evidences. European Journal of Pharmacology, 649, 229–235.

    Article  PubMed  Google Scholar 

  25. Pari, L., & Sivasankari, R. (2008). Effect of ellagic acid on cyclosporine A-induced oxidative damage in the liver of rats. Fundamental and Clinical Pharmacology, 22, 395–401.

    Article  PubMed  CAS  Google Scholar 

  26. Nihal, M., Ahmad, N., Mukhtar, H., & Wood, G. S. (2005). Anti-proliferative and proapoptotic effects of (−)-epigallocatechin-3-gallate on human melanoma: Possible implications for the chemoprevention of melanoma. International Journal of Cancer, 114, 513–521.

    Article  CAS  Google Scholar 

  27. Oltvai, Z. N., Milliman, C. L., & Korsmeyer, S. J. (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell, 74, 609–619.

    Article  PubMed  CAS  Google Scholar 

  28. Ling, H., & Lou, Y. (2005). Total flavones from Elsholtzia blanda reduce infarct size during acute myocardial ischemia by inhibiting myocardial apoptosis in rats. Journal of Ethnopharmacology, 101, 169–175.

    Article  PubMed  CAS  Google Scholar 

  29. Prabhu, S. D., Wang, G., Luo, J., Gu, Y., Ping, P., & Chandrasekar, B. (2003). Beta-adrenergic receptor blockade modulates Bcl-X(S) expression and reduces apoptosis in failing myocardium. Journal of Molecular and Cellular Cardiology, 35, 483–493.

    Article  PubMed  CAS  Google Scholar 

  30. Kawai, K., Qin, F., Shite, J., Mao, W., Fukuoka, S., & Liang, C. S. (2004). Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy. American Journal of Physiology. Heart and Circulatory Physiology, 287, H1003–H1012.

    Article  PubMed  CAS  Google Scholar 

  31. Thomberry, N. A., & Lazebnik, Y. (1998). Caspases: Enemies within. Science, 281, 1312–1316.

    Article  Google Scholar 

  32. Zou, H., Henzel, W. J., Liu, X., Lutschg, A., & Wang, X. (1997). Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell, 90, 405–413.

    Article  PubMed  CAS  Google Scholar 

  33. Zou, H., Li, Y., Liu, X., & Wang, X. (1994). An APAF-1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. Journal of Biological Chemistry, 274, 11549–11556.

    Article  Google Scholar 

  34. Hwang, J. M., Cho, J. S., Kim, T. H., & Lee, Y. I. (2010). Ellagic acid protects hepatocytes from damage by inhibiting mitochondrial production of reactive oxygen species. Biomedicine and Pharmacotherapy, 64, 264–270.

    Article  CAS  Google Scholar 

  35. Malhotra, R., Lin, Z., Vincenz, C., & Brosius, F. C., 3rd. (2001). Hypoxia induces apoptosis via two independent pathways in Jurkat cells: differential regulation by glucose. American Journal of Physiology. Cell Physiology, 281, C1596–C1603.

    PubMed  CAS  Google Scholar 

  36. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., et al. (1999). Molecular characterization of mitochondrial apoptosis-inducing factor. Nature, 397, 441–446.

    Article  PubMed  CAS  Google Scholar 

  37. Senthilnathan, P., Padmavathi, R., Magesh, V., & Sakthisekaran, D. (2006). Modulation of TCA cycle enzymes and electron transport chain systems in experimental lung cancer. Life Sciences, 78, 1010–1014.

    Article  PubMed  CAS  Google Scholar 

  38. Vijayapadma, V., & Shyamaladevi, C. S. (2001). Effect of fish oil on mitochondrial respiration in isoproterenol induced myocardial infarction in rats. Indian Journal of Experimental Biology, 40, 268–272.

    Google Scholar 

  39. Ou, H. C., Lee, W. J., Lee, S. D., Huang, C. Y., Chiu, T. H., Tsai, K. L., et al. (2010). Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3 K/Akt/eNOS pathway. Toxicology and Applied Pharmacology, 248, 134–143.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. SASTRA University, Thirumalaisamudram, Thanjavur, Tamil Nadu, India

    M. Mari Kannan

  2. Department of Clinical Pharmacy and Pharmacology, Jayamukhi College of Pharmacy, Narsampet, Warangal, Andhra Pradesh, India

    M. Mari Kannan

  3. Post Graduate and Research Department of Chemistry, Government Arts College, C.Mutlur, Chidambaram, Tamil Nadu, India

    S. Darlin Quine

Authors
  1. M. Mari Kannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Darlin Quine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Darlin Quine.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mari Kannan, M., Darlin Quine, S. Mechanistic Clues in the Protective Effect of Ellagic Acid Against Apoptosis and Decreased Mitochondrial Respiratory Enzyme Activities in Myocardial Infarcted Rats. Cardiovasc Toxicol 12, 56–63 (2012). https://doi.org/10.1007/s12012-011-9138-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-011-9138-7

Keywords

Search

Navigation