Cardiovascular Toxicology

, Volume 19, Issue 1, pp 23–35 | Cite as

Beneficial Effect of Silymarin in Pressure Overload Induced Experimental Cardiac Hypertrophy

  • Basant Sharma
  • Udit Chaube
  • Bhoomika M. PatelEmail author


The present investigation was undertaken to study the effect of silymarin on cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) in Wistar rats. Silymarin was administered for 9 weeks at the end of which we evaluated hypertrophic, hemodynamic, non-specific cardiac markers, oxidative stress parameters, and determined mitochondrial DNA concentration. Hypertrophic control animals exhibited cardiac hypertrophy, altered hemodynamics, oxidative stress, and decreased mitochondrial DNA (mtDNA) concentration. Treatment with silymarin prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Docking studies revealed that silymarin produces maximum docking score with mitogen-activated protein kinases (MAPK) p38 as compared to other relevant proteins docked. Moreover, PAAC-control rats exhibited significantly increased expression of MAPK p38β mRNA levels which were significantly decreased by the treatment of silymarin. Our data suggest that silymarin produces beneficial effects on cardiac hypertrophy which are likely to be mediated through inhibition of MAPK p38β.


Partial abdominal aortic constriction (PAAC) Cardiac hypertrophy Silymarin MAPK p38 β Mitochondrial DNA 



Mean arterial blood pressure


Mitogen-activated protein kinases


Mitogen-activated protein kinase kinase kinase 5


Mitogen-activated protein kinase kinase 3/6


Partial abdominal aortic constriction


Sham control


Sham control animals treated with silymarin (50 mg/kg/day, p.o)


Sham control animals treated with silymarin (100 mg/kg/day, p.o)


Hypertrophic control


Hypertrophic animals treated with silymarin (50 mg/kg/day, p.o)


Hypertrophic animals treated with silymarin (100 mg/kg/day, p.o)


C-reactive protein


Lactate de-hydrogenase


Creatinine kinase


Rate of pressure development


Rate of pressure decay


Cardiac hypertrophic index


Left ventricular hypertrophic index


Left ventricular weight-to-right ventricular weight ratio


Heart weight-to-body weight ratio




Reduced glutathione


Superoxide dismutase


Mitochondrial DNA


Genetic optimization for ligand docking


c-Jun NH2 terminal kinases


Extracellular signal-regulated kinases




Protein data bank



The authors acknowledge Dr. Hardik Bhatt, Associate Professor, Department of Chemistry, Institute of Pharmacy, Nirma University for rendering required help in the docking studies.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interests.


  1. 1.
    Anan, R., Nakagawa, M., Miyata, M., Higuchi, I., Nakao, S., Suehara, M., et al. (1995). Cardiac involvement in mitochondrial diseases. A study on 17 patients with documented mitochondrial DNA defects. Circulation, 91(4), 955–961.Google Scholar
  2. 2.
    Andrews, C., Ho, P., Dillmann, W., Glembotski, C., & McDonoughc, P. (2003). The MKK6–p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT. Cardiovascular Research, 59, 46–56.Google Scholar
  3. 3.
    Anton, R., Bauer, S. M., Keck, P., & Laufer, P. (2014). A p38 Substrate-Specific MK2-EGFP translocation assay for identification and validation of new p38 inhibitors in living cells: A comprising alternative for acquisition of cellular p38 inhibition. PLoS ONE, 9, e95641.Google Scholar
  4. 4.
    Barja, G., & Herrero, A. (2000). Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heat and brain of mammals. The FASEB Journal, 14, 312–318.Google Scholar
  5. 5.
    Bernardo, B. C., Weeks, K. L., Pretorius, L., & McMullen Jr. (2010). Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies. Pharmacology & Therapeutics, 128, 191–227.Google Scholar
  6. 6.
    Borah, A., Paul, R., Choudhury, S., Choudhury, A., Bhuyan, B., Talukdar, D., A., et al (2013). Neuroprotective potential of silymarin against CNS disorders: Insight into the pathways and molecular mechanisms of action. CNS Neuroscience Therapeutics, 19, 847–853.Google Scholar
  7. 7.
    Buckley, D. I., Fu, R., Freeman, M., Rogers, K., & Helfand, M. (2009). C-reactive protein as a risk factor for coronary heart disease: A systematic review and meta-analyses for the U.S. Preventive Services Task Force. Annals of Internal Medicine, 151, 483–495.Google Scholar
  8. 8.
    Bugger, H., & Abel, E. D. (2010). Mitochondria in the diabetic heart. Cardiovascular Research, 88, 229–240.Google Scholar
  9. 9.
    Chen, P. N., Hsieh, Y. S., Chiou, H. L., & Chu, S. C. (2005). Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways. Chemico-Biological Interactions, 156(2–3), 141–150.Google Scholar
  10. 10.
    Dai, D. F., Johnson, S. C., Villarin, J. J., Chin, M. T., Nieves-Cintron, M., Chen, T., et al. (2011). Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circulation Research, 108, 837–846.Google Scholar
  11. 11.
    Dhalla, N. S., Temsah, R. M., & Netticadan, T. (2000). Role of oxidative stress in cardiovascular diseases. Journal of Hypertension, 18, 655–673.Google Scholar
  12. 12.
    Dickhout, J. G., Carlisle, R. E., & Austin, R. C. (2011). Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: Endoplasmic reticulum stress as a mediator of pathogenesis. Circulation Research, 108(5), 629–642.Google Scholar
  13. 13.
    Elkamhawy, A., Lee, J., Park, B. G., Park, I., Pae, A. N., & Roh, E. J. (2014). Novel quinazoline-urea analogues as modulators for Aβ-induced mitochondrial dysfunction: Design, synthesis, and molecular docking study. European Journal of Medicinal Chemistry, 84, 466–475.Google Scholar
  14. 14.
    Frey, N., & Olson, E. N. (2003). Cardiac hypertrophy: The good, the bad, and the ugly. Annual Review of Physiology, 65, 45–79.Google Scholar
  15. 15.
    Gabrielová, E., Zholobenko, A. V., Bartošíková, L., Nečas, J., & Modriansky, M. (2015). Silymarin constituent 2,3-dehydrosilybin triggers reserpine-sensitive positive inotropic effect in perfused rat heart. PLoS ONE, 10(9), e0139208.Google Scholar
  16. 16.
    Gharagozloo, M., Jafari, S., Esmaeil, N., Javid, E. N., Bagherpour, B., & Rezaei, A. (2013). Immunosuppressive effect of silymarin on mitogen-activated protein kinase signalling pathway: The impact on T cell proliferation and cytokine production. Basic & Clinical Pharmacology & Toxicology, 113, 209–214.Google Scholar
  17. 17.
    Goyal, B. R., & Mehta, A. A. (2012). Beneficial role of spironolactone, telmisartan and their combination on isoproterenol induced cardiac hypertrophy. Acta Cardiologica, 67, 203–211.Google Scholar
  18. 18.
    Goyal, B. R., & Mehta, A. A. (2013). Diabetic cardiomyopathy: Pathophysiological mechanisms and cardiac dysfunction. Human & Experimental Toxicology, 32, 571–590.Google Scholar
  19. 19.
    Goyal, B. R., Mesariya, P., Goyal, R. K., & Mehta, A. A. (2008). Effect of telmisartan on cardiovascular complications associated with streptozotocin diabetic rats. Molecular and Cellular Biochemistry, 314, 123–131.Google Scholar
  20. 20.
    Goyal, B. R., Parmar, K., Goyal, R. K., & Mehta, A. A. (2011). Beneficial role of telmisartan on cardiovascular complications associated with STZ-induced type-2 diabetic rats. Pharmacological Reports, 63, 956–966.Google Scholar
  21. 21.
    Goyal, B. R., Patel, M. M., & Bhadada, S. V. (2011). Comparative evaluation of spironolactone, atenolol, metoprolol, ramipril and perindopril on diabetes induced cardiovascular complications in type 1 diabetes in rats. International Journal of Diabetes and Metabolism, 19, 11–18.Google Scholar
  22. 22.
    Goyal, B. R., Solanki, N., Goyal, R. K., & Mehta, A. A. (2009). Investigation into the cardiac effects of spironolactone in the experimental model of type 1 diabetes. Journal of Cardiovascular Pharmacology, 54, 502–509.Google Scholar
  23. 23.
    Hakan, A. Y., Arsava, M., & Okay, S. (2002). Creatine kinase-MB elevation after stroke is not cardiac in origin. Stroke 33, 286–290.Google Scholar
  24. 24.
    Horton, J. W., Tan, J., White, J., & Maass, D. (2007). Burn injury decreases myocardial Na- K-ATPase activity: Role of PKC inhibition. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 293, R1684–R1692.Google Scholar
  25. 25.
    Huang, Q., Wu, L. J., Tashiro, S., Onodera, S., Li, L. H., & Ikejima, T. (2005). Silymarin augments human cervical cancer HeLa cell apoptosis via P38/JNK MAPK pathways in serum-free medium. Journal of Asian Natural Products Research, 7(5), 701–709.Google Scholar
  26. 26.
    Karamanlidis, G., Bautista-Hernandez, V., Fynn-Thompson, F., Del Nido, P., & Tian, R. (2011). Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease. Circulation: Heart Failure, 4, 707–713.Google Scholar
  27. 27.
    Katholi, R. E., & Couri, D. M. (2011). Left ventricular hypertrophy: Major risk factor in patients with hypertension: Update and practical clinical applications. International Journal of Hypertension. Google Scholar
  28. 28.
    Kumphune, S., Chattipakorn, S., & Chattipakorn, N. (2012). Role of p38 inhibition in cardiac ischemia/reperfusion injury. European Journal of Clinical Pharmacology, 68, 513–524.Google Scholar
  29. 29.
    Lee, J. K., & Kim, N. J. (2017). Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease. Molecules, 22(8), E1287.Google Scholar
  30. 30.
    Li, P. C., Chiu, Y. W., Lin, M. Y., Day, H. C., Hwang, G. Y., Pai, P., Tsai, F. J., Tsai, C. H., Kuo, Y. C., Chang, H. C., Liu, J. Y., & Huang, C. Y. (2012). Herbal supplement ameliorates cardiac hypertrophy in rats with -induced liver cirrhosis. Evidence-Based Complementary and Alternative Medicine. Google Scholar
  31. 31.
    Molkentin, J. D., & Dorn, G. W. (2001). Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annual Review of Physiology, 63, 391–426.Google Scholar
  32. 32.
    Patel, B. M. (2018). Sodium butyrate controls cardiac hypertrophy in experimental models of rats. Cardiovascular Toxicology, 18(1), 1–8.Google Scholar
  33. 33.
    Patel, B. M., Agarwal, S. S., & Bhadada, S. V. (2012). Perindopril protects against streptozotocin induced hyperglycemic myocardial damage/alterations. Human & Experimental Toxicology, 31(11), 1138–1149.Google Scholar
  34. 34.
    Patel, B. M., & Desai, V. J. (2014). Beneficial role of tamoxifen in experimentally induced cardiac hypertrophy. Pharmacological Reports, 66, 264–272.Google Scholar
  35. 35.
    Patel, B. M., & Bhadada, S. V. (2014). Type 2 diabetes induced cardiovascular complications: Comparative evaluation of spironolactone, atenolol, metoprolol, ramipril and perindopril. Clinical and Experimental Hypertension, 36, 340–347.Google Scholar
  36. 36.
    Patel, B. M., Kakadiya, J., Goyal, R. K., & Mehta, A. A. (2013). Effect of spironolactone on cardiovascular complications associated with type-2 diabetes in rats. Experimental and Clinical Endocrinology, 121, 441–447.Google Scholar
  37. 37.
    Patel, B. M., Mehta, A. A. (2013). The choice of anti-hypertensive agents in diabetic subjects. Diabetes and Vascular Disease Research, 10, 385–396.Google Scholar
  38. 38.
    Patel, B. M., & Mehta, A. A. (2012). Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases. European Journal of Pharmacology, 697, 1–12.Google Scholar
  39. 39.
    Patel, B. M., Raghunathan, S., & Porwal, U. (2014). Cardioprotective effects of magnesium valproate in type 2 diabetes mellitus. European Journal of Pharmacology, 728, 128–134.Google Scholar
  40. 40.
    Peppers, V., Ramos, G., Manias, E., Koroboki, E., Rokas, S., & Zakopoulos, N. (2008). Correlation between myocardial enzyme serum levels and markers of inflammation with severity of coronary artery disease and Gensini score: A hospital-based prospective study in Greek patients. Clinical Interventions in Aging, 3, 699–710.Google Scholar
  41. 41.
    Post-White, J., Ladas, E. J., & Kelly, K. M. (2007). Advances in the use of milk thistle (Silybum marianum). Integrative Cancer Therapies, 6, 104–109.Google Scholar
  42. 42.
    Prockop, D. J., & Udenfriend, S. (1960). A specific method for the analysis of hydroxyproline in tissues and urine. Analytical Biochemistry, 1, 228–239.Google Scholar
  43. 43.
    Raghunathan, S., & Patel, B. M. (2013). Therapeutic implications of small interfering RNA in cardiovascular diseases. Fundamental and Clinical Pharmacology, 27, 1–20.Google Scholar
  44. 44.
    Rao, P. R., & Viswanath, R. K. (2007). Cardioprotective activity of silymarin in ischemia-reperfusion-induced myocardial infarction in albino rats. Experimental & Clinical Cardiology, 12, 179–187.Google Scholar
  45. 45.
    Rayabarapu, N., & Patel, B. M. (2014). Beneficial role of tamoxifen in isoproterenol induced myocardial infarction. Canadian Journal of Physiology and Pharmacology, 92, 849–857.Google Scholar
  46. 46.
    Rosca, M. G., Tandler, B., & Hoppel, C. L. (2013). Mitochondria in cardiac hypertrophy and heart failure. Journal of Molecular and Cellular Cardiology, 55, 31–41.Google Scholar
  47. 47.
    Rose, B. A., Force, T., & Wang, Y. (2010). Mitogen-activated protein kinase signaling in the heart: Angels versus demons in a heart-breaking tale. Physiological Reviews, 90, 1507–1546.Google Scholar
  48. 48.
    Sakottova, N., Vecera, R., Urbenek, K., Vana, P., Walterova, D., & Cvak, L. (2003). Effects of polyphenolic fraction of silymarin on lipoprotein profile in rats fed cholesterol-rich diets. Pharmacological Research, 47, 17–26.Google Scholar
  49. 49.
    Sanz-Moreno, V., & Crespo, P. (2003). p38 mitogen-activated protein kinases: Their role in carcinogenesis. Revista de oncología, 5, 320–330.Google Scholar
  50. 50.
    Thakare, V. N., Aswar, M. K., Kulkarni, Y. P., Patil, R. R., & Patel, B. M. (2017). Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response. Physiology & Behavior, 179, 401–410.Google Scholar
  51. 51.
    Thakare, V. N., Dhakane, V. D., & Patel, B. M. (2016). Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus. Pharmacological Reports, 68, 1020–1027.Google Scholar
  52. 52.
    Thakare, V. N., Patil, R. R., Oswal, R. J., Dhakane, V. D., Aswar, M. K., & Patel, B. M. (2018). Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice. Journal of Psychopharmacology, 32, 223–235.Google Scholar
  53. 53.
    Tsimaratos, M., Coste, T. C., Djemli-Shipkolye, A., Daniel, L., Shipkolye, F., Vague, P., & Raccah, D. (2001). Evidence of time-dependent changes in renal medullary Na,K-ATPase activity and expression in diabetic rats. Cellular Molecular Biology (Noisy-le-grand), 47, 239–245.Google Scholar
  54. 54.
    Tuorkey, M. J., El-Desouki, N. I., & Kamel, R. A. (2015). Cytoprotective effect of Silymarin against diabetes-induced cardiomyocyte apoptosis in diabetic rats. Biomedical and Environmental Sciences, 28(1), 36–43.Google Scholar
  55. 55.
    Wang, Y., Huang, S., Sah, V. P., Ross, J., Brown, J. H., Han, J., & Chien, K. R. (1998). Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. Journal of Biological Chemistry, 273, 2161–2168.Google Scholar
  56. 56.
    Wu, J. H., Hagaman, J., Kim, S., Reddick, R. L., & Maeda, N. (2002). Aortic constriction exacerbates atherosclerosis and induces cardiac dysfunction in mice lacking apolipoprotein E. Arteriosclerosis, Thrombosis, and Vascular Biology, 22(3), 469–475.Google Scholar
  57. 57.
    Zhang, S., Weinheimer, C., Courtois, M., Kovacs, A., Zhang, C. E., Cheng, A. M., Wang, Y., & Muslin, A. J. (2003). The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. Journal of Clinical Investigation, 111, 833–841.Google Scholar
  58. 58.
    Zholobenko, A., & Modriansky, M. (2014). Silymarin and its constituents in cardiac preconditioning. Fitoterapia, 97, 122–132.Google Scholar
  59. 59.
    Zhou, B., Wu, L. J., Tashiro, S., Onodera, S., Uchiumi, F., & Ikejima, T. (2007). Activation of extracellular signal-regulated kinase during silibinin-protected, isoproterenol-induced apoptosis in rat cardiac myocytes is tyrosine kinase pathway-mediated and protein kinase C-dependent. Acta Pharmacologica Sinica, 28(6), 803–810.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of PharmacyNirma UniversityAhmedabadIndia

Personalised recommendations