Skip to main content

Advertisement

SpringerLink
Log in

Beneficial Effect of Silymarin in Pressure Overload Induced Experimental Cardiac Hypertrophy

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

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.

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

Similar content being viewed by others

Abbreviations

MABP:

Mean arterial blood pressure

MAPK:

Mitogen-activated protein kinases

MAP3K5:

Mitogen-activated protein kinase kinase kinase 5

MKK3/6:

Mitogen-activated protein kinase kinase 3/6

PAAC:

Partial abdominal aortic constriction

CON:

Sham control

COS50:

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

COS100:

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

HYP:

Hypertrophic control

HYS50:

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

HYS100:

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

CRP:

C-reactive protein

LDH:

Lactate de-hydrogenase

CK:

Creatinine kinase

dp/dtmax:

Rate of pressure development

dp/dtmin:

Rate of pressure decay

CHI:

Cardiac hypertrophic index

LVHI:

Left ventricular hypertrophic index

LVW/RVW:

Left ventricular weight-to-right ventricular weight ratio

HW/BW:

Heart weight-to-body weight ratio

MDA:

Malondialdehyde

GSH:

Reduced glutathione

SOD:

Superoxide dismutase

mtDNA:

Mitochondrial DNA

GOLD:

Genetic optimization for ligand docking

JNK1/2/3:

c-Jun NH2 terminal kinases

ERK1/2:

Extracellular signal-regulated kinases

HMG-CoA:

3-Hydroxy-3-methylglutaryl-coenzyme

PDB:

Protein data bank

References

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  8. Bugger, H., & Abel, E. D. (2010). Mitochondria in the diabetic heart. Cardiovascular Research, 88, 229–240.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  11. Dhalla, N. S., Temsah, R. M., & Netticadan, T. (2000). Role of oxidative stress in cardiovascular diseases. Journal of Hypertension, 18, 655–673.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  14. Frey, N., & Olson, E. N. (2003). Cardiac hypertrophy: The good, the bad, and the ugly. Annual Review of Physiology, 65, 45–79.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  18. Goyal, B. R., & Mehta, A. A. (2013). Diabetic cardiomyopathy: Pathophysiological mechanisms and cardiac dysfunction. Human & Experimental Toxicology, 32, 571–590.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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. https://doi.org/10.4061/2011/495349

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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. https://doi.org/10.1155/2012/139045

    Article  PubMed  PubMed Central  Google Scholar 

  31. Molkentin, J. D., & Dorn, G. W. (2001). Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annual Review of Physiology, 63, 391–426.

    Article  CAS  Google Scholar 

  32. Patel, B. M. (2018). Sodium butyrate controls cardiac hypertrophy in experimental models of rats. Cardiovascular Toxicology, 18(1), 1–8.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  34. Patel, B. M., & Desai, V. J. (2014). Beneficial role of tamoxifen in experimentally induced cardiac hypertrophy. Pharmacological Reports, 66, 264–272.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  38. Patel, B. M., & Mehta, A. A. (2012). Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases. European Journal of Pharmacology, 697, 1–12.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  42. Prockop, D. J., & Udenfriend, S. (1960). A specific method for the analysis of hydroxyproline in tissues and urine. Analytical Biochemistry, 1, 228–239.

    Article  CAS  Google Scholar 

  43. Raghunathan, S., & Patel, B. M. (2013). Therapeutic implications of small interfering RNA in cardiovascular diseases. Fundamental and Clinical Pharmacology, 27, 1–20.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  49. Sanz-Moreno, V., & Crespo, P. (2003). p38 mitogen-activated protein kinases: Their role in carcinogenesis. Revista de oncología, 5, 320–330.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  58. Zholobenko, A., & Modriansky, M. (2014). Silymarin and its constituents in cardiac preconditioning. Fitoterapia, 97, 122–132.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, 382 481, India

    Basant Sharma, Udit Chaube & Bhoomika M. Patel

Authors
  1. Basant Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Udit Chaube
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bhoomika M. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhoomika M. Patel.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Additional information

Handling Editor: Lorraine Chalifour.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, B., Chaube, U. & Patel, B.M. Beneficial Effect of Silymarin in Pressure Overload Induced Experimental Cardiac Hypertrophy. Cardiovasc Toxicol 19, 23–35 (2019). https://doi.org/10.1007/s12012-018-9470-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-018-9470-2

Keywords

Search

Navigation