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Anti-Atherogenic Protection by Oligomeric Proanthocyanidins via Regulating Collagen Crosslinking Against CC Diet-Induced Atherosclerosis in Rats

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Abstract

The synthesis of collagen and its turnover remained as critical determinants for the progression of atherosclerosis. During this condition, proteases secreted by SMCs and foam cells in the necrotic core degrade collagen. Growing evidences demonstrated that consumption of antioxidant rich diet is highly associated with a reduced risk of atherosclerosis. Oligomeric proanthocyanidins (OPC) have been proved to possess promising antioxidant, anti-inflammatory and cardioprotective activity, based on our previous studies. The present study aims to investigate the efficacy of OPC isolated from Crataegus oxyacantha berries as a natural collagen crosslinker and anti-atherogenic agent. Spectral studies like FTIR, ultraviolet and circular dichroism analysis confirmed the in vitro crosslinking ability of OPC with rat tail collagen when compared to the standard epigallocatechin gallate. The administration of cholesterol:cholic acid (CC) diet induces proteases-mediated collagen degradation that could result in plaque instability. Further, the CC diet fed rats showed significantly increased levels of total cholesterol and triacylglycerols which, in turn, increases the activities of collagen degrading proteases-MMPs (MMP 1, 2 and 9) and Cathepsin S and D. Upon OPC treatment, marked reduction in the lipid content, activation of proteases with concomitant increase in the mRNA levels of collagen Type I and Type III as similar to atorvastatin treatment were observed .Thus, OPC supplementation may contribute to the prevention of atherosclerotic plaque instability by acting as a natural crosslinker of collagen.

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Data and results have been generated as part of my doctoral thesis work.

References

  1. Wu, M. Y., Li, C. J., Hou, M. F., & Chu, P. Y. (2017). New insights into the role of inflammation in the pathogenesis of atherosclerosis. International Journal of Molecular Sciences, 18(10), 2034.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hernandez-Anzaldo, S., Brglez, V., Hemmeryckx, B., Leung, D., Filep, J. G., Vance, J. E., Vance, D. E., Kassiri, Z., Lijnen, R. H., Lambeau, G., & Fernandez-Patron, C. (2016). Novel role for matrix metalloproteinase 9 in modulation of cholesterol metabolism. Journal of the American Heart Association., 5(10), e004228.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu, H., Du, Q., Dai, Q., Ge, J., & Cheng, X. (2018). Cysteine protease cathepsins in atherosclerotic cardiovascular diseases. Journal of Atherosclerosis and Thrombosis, 25(2), 111–123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Libby, P. (2009). Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis. Journal of Lipid Research, 50, S352–S357.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Moore, K., Sheedy, F., & Fisher, E. (2013). Macrophages in atherosclerosis: A dynamic balance. Nature Reviews Immunology, 13(10), 709–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Paigen, B., Morrow, A., Brandon, C., Mitchell, D., & Holmes, P. (1985). Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis, 57(1985), 65–73.

    Article  CAS  PubMed  Google Scholar 

  7. Sankar, J., Rathinavel, A., Sakeena Sadullah, M. S., & Devaraj, S. N. (2018). Oligomeric proanthocyanidins mitigate cholesterol and cholic acid diet–induced hepatic dysfunction in male Sprague Dawley rats. Journal of Biochemical and Molecular Toxicology, 33, e22234.

    Google Scholar 

  8. Getz, G. S., & Reardon, C. A. (2012). Animal models of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(5), 1104–1115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rathinavel, A., Sankar, J., Mohammed Sadullah, S. S., & Niranjali Devaraj, S. (2018). Oligomeric proanthocyanidins protect myocardium by mitigating left ventricular remodeling in isoproterenol-induced postmyocardial infarction. Fundamental & Clinical Pharmacology, 32(1), 51–59.

    Article  CAS  Google Scholar 

  10. Gabetta, B., Fuzzati, N., Griffino, A., Lolla, E., Pace, R., Ruffilli, T., & Peterlongo, F. (2000). Characterization of procyanidins from grape seeds (Leucoselect). Fitoterapia, 71(2), 162–175.

    Article  CAS  PubMed  Google Scholar 

  11. Mohana, T., Navin, A. V., Jamuna, S., Sakeena Sadullah, M. S., & Niranjali Devaraj, S. (2015). Inhibition of differentiation of monocyte to macrophages in atherosclerosis by oligomeric proanthocyanidins—In-vivo and in-vitro study. Food and Chemical Toxicology, 82, 96–105.

    Article  CAS  PubMed  Google Scholar 

  12. Rathinavel, A., Jamuna, S., & Sadullah, S. S. M. Sivasitambaram Niranjali Devaraj Oligomeric proanthocyanidins protect myocardium by mitigating left ventricular remodeling in Isoproterenol induced post-myocardial infarction. Fundamental and Clinical Pharmacology, 32(1), 51–59.

  13. Jamuna, S., Rathinavel, A., Sadullah, S. S. M., & Devaraj, S. N. (2019). Oligomeric proanthocyanidins and epigallocatechin gallate aggravate autophagy of foam cells through the activation of Class III PI3K/Beclin1-complex mediated cholesterol efflux. Biofactors, 45(5), 763–777.

    Article  CAS  PubMed  Google Scholar 

  14. Jamuna, S., Ashokkumar, R., & Devaraj, S. N. (2022). Amelioration of C - reactive protein and lectin like oxidised low density lipoprotein receptor complex induced endothelial dysfunction by oligomeric proanthocyanidins. Biotechnology and Applied Biochemistry. https://doi.org/10.1007/s12010-021-03792-6

  15. Huang, C., Cen, C., Wang, C., Zhan, H., & Ding, X. (2014). Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia. Lipids in Health and Disease, 13, 67.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Woessner, J. F. (1961). The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Archives of Biochemistry and Biophysics, 93(1961), 440447.

    Google Scholar 

  17. Sapolsky, A. I., Altman, R. D., & Howell, D. S. (1973). Cathepsin D activity in normal and osteoarthritic human cartilage. Federation Proceedings, 32, 1489–1493.

    CAS  PubMed  Google Scholar 

  18. Tattini, V., Jr., Matos, J. D. R., Polakiewicz, B., & Pitombo, R. N. D. M. (2007). Evaluation of shrinkage temperature of bovine pericardium tissue for bioprosthetic heart valve application by differential scanning calorimetry and freeze-drying microscopy. Materials Research, 10(1), 1–4.

    Article  CAS  Google Scholar 

  19. Chomczynski, P., & Sacchi, N. (1987). Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry, 162, 156–159.

    Article  CAS  PubMed  Google Scholar 

  20. Slätis, K., Gåfvels, M., Kannisto, K., et al. (2010). Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice. Journal of Lipid Research, 51(11), 3289–3298.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Minatti, J., Wazlawik, E., Hort, M. A., Zaleski, F. L., Ribeiro-do-Valle, R. M., Maraschin, M., et al. (2012). Green tea extract reverses endothelial dysfunction and reduces atherosclerosis progression in homozygous knockout low-density lipoprotein receptor mice. Nutrition Research, 32(9), 684–693.

    Article  CAS  PubMed  Google Scholar 

  22. Suzanne, P. M., Lutgens Kitty, B. J. M., & Cleutjens Mat, J. A. P. (2007). Daemen and Sylvia Heeneman. Cathepsin cysteine proteases in cardiovascular disease. The FASEB Journal, 21(12), 3029–3041.

    Article  Google Scholar 

  23. Sáez, P., Peña, E., Tarbell, J. M., & Martínez, M. A. (2015). Computational model of collagen turnover in carotid arteries during hypertension. International Journal for Numerical Methods in Biomedical Engineering, 31(2), 02705.

    Article  Google Scholar 

  24. Vidak, E., Javoršek, U., Vizovišek, M., & Turk, B. (2019). Cysteine cathepsins and their extracellular roles: Shaping the microenvironment. Cells, 8(3), 264. https://doi.org/10.3390/cells8030264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hakala, J. K., et al. (2003). Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 1430–1436.

    Article  CAS  PubMed  Google Scholar 

  26. Jan, B., John Chapman, M., Krauss, R. M., et al. (2020). Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal, 41(24), 2313–2330.

    Article  Google Scholar 

  27. Zhang, Y., Breevoort, S. R., Angdisen, J., Fu, M., Schmidt, D. R., Holmstrom, S. R., Kliewer, S. A., Mangelsdorf, D. J., & Schulman, I. G. (2012). Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. Journal of Clinical Investigation, 122, 1688–1699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Raffetto, J. D., & Khalil, R. A. (2008). Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochemical Pharmacology, 75(2), 346–359.

    Article  CAS  PubMed  Google Scholar 

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Funding

Authors would like to acknowledge the University Grants Commission (UGC), New Delhi, India, for financial support under UGC-BSR meritorious fellowship.

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Contributions

SJ, AKR and SND: study conception, experimental design, analysis and interpretation of data. SJ and AKR: drafting the article, ISR analysis of biophysical parameters and interpretation and SND revising and final approval of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sivasitamparam Niranjali Devaraj.

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The experiments were conducted with the ethical norms approved by the Institutional Animal Ethics Committee (IAEC No: 01/03/2012).

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Jamuna, S., Ashokkumar, R., Raja, I.S. et al. Anti-Atherogenic Protection by Oligomeric Proanthocyanidins via Regulating Collagen Crosslinking Against CC Diet-Induced Atherosclerosis in Rats. Appl Biochem Biotechnol 195, 4881–4892 (2023). https://doi.org/10.1007/s12010-023-04487-w

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