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Impact of Pycnogenol® on cardiac extracellular matrix remodeling induced by l-NAME administration to old mice

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Abstract

Cardiac remodeling is a determinant of the clinical progression of heart failure and now slowing or reversing remodeling is considered as a potential therapeutic target in heart failure. Pycnogenol® has been reported to mediate a number of beneficial effects in the cardiovascular system but its effects on hemodynamic and functional cardiovascular changes following cardiac remodeling have not been elucidated. Therefore, we investigated the influence of Pycnogenol® supplementation (30 mg/kg) on left ventricular function and myocardial extracellular matrix composition in old C57BL/6N mice following induction of cardiac remodeling by chronic nitric oxide synthase blockade by N G-nitro-l-arginine methyl ester (l-NAME) administration. l-NAME-treated mice demonstrated dilated cardiomyopathy at compensated state, associated with a significant increase of pro-matrix metalloproteinase (MMP)-9 gene expression and activity, a marked decrease in pro-collagen IIIα1 gene expression, and a subsequent reduction in cardiac total and cross-linked collagen content. Upon supplementation with Pycnogenol® in l-NAME-exposed mice, cardiac gene expression patterns for pro-MMP-2, -9, and -13, and MMP-9 activity were significantly decreased, associated with a significant increase in cardiac tissue inhibitor of metalloproteinase (TIMP)-4 expression. These findings were coincided with a marked increase in myocardial total and cross-linked collagen content, compared with l-NAME-only-treated mice. Moreover, Pycnogenol® treatment was associated with reversal of l-NAME-induced alternations in hemodynamic parameters. These data indicate that Pycnogenol® can prevent adverse myocardial remodeling induced by l-NAME, through modulating TIMP and MMPs gene expression, MMPs activity, and further reduction in myocardial collagen degradation rate.

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References

  1. Araghi-Niknam, M., Hosseini, S., Larson, D., Rohdewald, P., & Watson, R. R. (2000). Pine bark extract reduces platelet aggregation. Integrative Medicine: Integrating Conventional and Alternative Medicine, 2, 73–77.

    Google Scholar 

  2. Barnes, P. J., & Larin, M. (1997). Mechanisms of disease – Nuclear factor-kappa b – A pivotal transcription factor in chronic inflammatory diseases. New England Journal of Medicine, 336, 1066–1071.

    Article  PubMed  CAS  Google Scholar 

  3. Belch, J. J. F., Bridges, A. B., Scott, N., & Chopra, M. (1991). Oxygen free-radicals and congestive-heart-failure. British Heart Journal, 65, 245–248.

    PubMed  CAS  Google Scholar 

  4. Bernatova, I., Pechanova, O., Pelouch, V., & Simko, F. (2000). Regression of chronic l-NAME-treatment-induced left ventricular hypertrophy: Effect of captopril. Journal of Molecular and Cellular Cardiology, 32, 177–185.

    Article  PubMed  CAS  Google Scholar 

  5. Blazso, G., Gaspar, R., Gábor, M., Rüve, H. J., & Rohdewald, P. (1996). ACE inhibition and hypotensive effect of procyanidins-containing extract from the bark of Pinus pinaster sol. Pharmacy Pharmacology Letters, 6, 8–11.

    Google Scholar 

  6. Bozkurt, B., Kribbs, S. B., Clubb, F. J., Michael, L. H., Didenko, V. V., Hornsby, P. J., Seta, Y., Oral, H., Spinale, F. G., & Mann, D. L. (1998). Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation, 97, 1382–1391.

    PubMed  CAS  Google Scholar 

  7. Bryant, D., Becker, L., Richardson, J., Shelton, J., Franco, F., Peshock, R., Thompson, M., & Giroir, B. (1998). Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation, 97, 1375–1381.

    PubMed  CAS  Google Scholar 

  8. Cheshier, J. E., ArdestaniKaboudanian, S., Liang, B. L., Araghiniknam, M., Chung, S. B., Lane, L., Castro, A., & Watson, R. R. (1995). Immunomodulation by Pycnogenol (R) in retrovirus-infected or ethanol-fed mice. Life Sciences, 58, L87–L96.

    Article  Google Scholar 

  9. Chiariello, M., Ambrosio, G., Cappelli-Bigazzi, M., Perrone-Filardi, P., Brigante, F., & Sifola, C. (1986). A biochemical method for the quantitation of myocardial scarring after experimental coronary artery occlusion. Journal of Molecular and Cellular Cardiology, 18, 283–290.

    Article  PubMed  CAS  Google Scholar 

  10. Cohn, J. N., Ferrari, R., & Sharpe, N. (2000). Cardiac remodeling-concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Journal of the American College of Cardiology, 35, 569–582.

    Article  PubMed  CAS  Google Scholar 

  11. Devaraj, S., Vega-Lopez, S., Kaul, N., Schonlau, F., Rohdewald, P., & Jialal, I. (2002). Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile. Lipids, 37, 931–934.

    Article  PubMed  CAS  Google Scholar 

  12. Dhalla, A. K., Hill, M. F., & Singal, P. K. (1996). Role of oxidative stress in transition of hypertrophy to heart failure. Journal of the American College of Cardiology, 28, 506–514.

    Article  PubMed  CAS  Google Scholar 

  13. Droge, W., Mihm, S., Bockstette, M., & Roth, S. (1994). Effect of reactive oxygen intermediates and antioxidants on proliferation and function of T-lymphocytes. Methods in Enzymology, 234, 135–151.

    Article  PubMed  CAS  Google Scholar 

  14. Duarte, J., Jimenez, R., O’Valle, F., Galisteo, M., Perez-Palencia, R., Vargas, F., Perez-Vizcaino, F., Zarzuelo, A., & Tamargo, J. (2002). Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. Journal of Hypertension, 20, 1843–1854.

    Article  PubMed  CAS  Google Scholar 

  15. Fedak, P. W. M., Verma, S., Weisel, R. D., & Li, R. K. (2005). Cardiac remodeling and failure – From molecules to man (Part II). Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology, 14, 49–60.

    CAS  Google Scholar 

  16. Fitzpatrick, D. F., Bing, B., & Rohdewald, P. (1998). Endothelium-dependent vascular effects of Pycnogenol. Journal of Cardiovascular Pharmacology, 32, 509–515.

    Article  PubMed  CAS  Google Scholar 

  17. Grimm, T., Chovanova, Z., Muchova, J., Sumegova, K., Liptakova, A., Durackova, Z., & Hogger, P. Inhibition of NF-kappaB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol). Journal of Inflammation (London), 3, 1, 2006 [Epub ahead of print].

    Google Scholar 

  18. Grimm, T., Schafer, A., & Hogger, P. (2004). Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol). Free Radical Biology & Medicine, 36, 811–822.

    Article  CAS  Google Scholar 

  19. Gunja-Smith, Z., Morales, A. R., Romanelli, R., & Woessner, J. F. (1996). Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy – Role of metalloproteinases and pyridinoline cross-links. American Journal of Pathology, 148, 1639–1648.

    PubMed  CAS  Google Scholar 

  20. Hosseini, S., Lee, J., Sepulveda, R. T., Rohdewald, P., & Watson, R. R. (2001). A randomized, double-blind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients. Nutrient Research, 21, 1251–1260.

    Article  CAS  Google Scholar 

  21. Kim, H. E., Dalal, S. S., Young, E., Legato, M. J., Weisfeldt, M. L., & D’Armiento, J. (2000). Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. The Journal of Clinical Investigation, 106, 857–866.

    PubMed  CAS  Google Scholar 

  22. Mallat, Z., Philip, I., Lebret, M., Chatel, D., Maclouf, J., & Tedgui, A. (1998). Elevated levels of 8-iso-prostaglandin F-2 alpha in pericardial fluid of patients with heart failure – A potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation, 97, 1536–1539.

    PubMed  CAS  Google Scholar 

  23. Matsunaga, T., Weihrauch, D. W., Moniz, M. C., Tessmer, J., Warltier, D. C., & Chilian, W. M. (2002). Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide. Circulation, 105, 2185–2191.

    Article  PubMed  CAS  Google Scholar 

  24. Nakamura, K., Kusano, K., Nakamura, Y., Kakishita, M., Ohta, K., Nagase, S., Yamamoto, M., Miyaji, K., Saito, H., Morita, H., Emori, T., Matsubara, H., Toyokuni, S., & Ohe, T. (2002). Carvedilol decreases elevated oxidative stress in human failing myocardium. Circulation, 105, 2867–2871.

    Article  PubMed  CAS  Google Scholar 

  25. Nelson, K. K., & Melendez, J. A. (2004). Mitochondrial redox control of matrix metalloproteinases. Free Radical Biology & Medicine, 37, 768–784.

    Article  CAS  Google Scholar 

  26. Packer, L., Rimbach, G., & Virgili, F. (1999). Antioxidant activity and biologic properties of a procyanidin-rich extract from the pine (Pinus maritima) bark, Pycnogenol. Free Radical Biology & Medicine, 27, 704–724.

    Article  CAS  Google Scholar 

  27. Paulus, W. J. (2000). Cytokines and heart failure. Heart Failure Monitor, 1, 50–56.

    PubMed  CAS  Google Scholar 

  28. Peterson, J. T., Hallak, H., Johnson, L., Li, H., O’Brien, P. M., Sliskovic, D. R., Bocan, T. M. A., Coker, M. L., Etoh, T., & Spinale, F. G. (2001). Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation, 103, 2303–2309.

    PubMed  CAS  Google Scholar 

  29. Rohdewald, P. J. (2005). Pycnogenol®, French maritime pine bark extract. In P. Coates, MR Blackman, G Cragg, M Levine, J Moss, & J. White (Eds.), Encyclopedia of dietary supplements (pp. 545–553). New York: Marcel Dekker.

  30. Schafer, A., Chovanova, Z., Muchova, J., Sumegova, K., Liptakova, A., Durackova, Z., & Hogger, P. (2006). Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol). Biomedicine & Pharmacotherapy, 60, 5–9.

    Article  Google Scholar 

  31. Spinale, F. G. (2004). Matrix metalloproteinase gene polymorphisms in heart failure: New pieces to the myocardial matrix puzzle. European Heart Journal, 25, 631–633.

    Article  PubMed  CAS  Google Scholar 

  32. Stegeman, H., & Stalder, K. (1967). Determination of Hydroxyproline. Clinica Chimica Acta; International Journal of Clinical Chemistry, 18, 267–273.

    Google Scholar 

  33. Testa, M., Yeh, M., Lee, P., Fanelli, R., Loperfido, F., Berman, J. W., & LeJemtel, T. H. (1996). Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. Journal of the American College of Cardiology, 28, 964–971.

    Article  PubMed  CAS  Google Scholar 

  34. Thomas, C. V., Coker, M. L., Zellner, J. L., Handy, J. R., Crumbley, A. J., & Spinale, F. G. (1998). Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation, 97, 1708–1715.

    PubMed  CAS  Google Scholar 

  35. TorreAmione, G., Kapadia, S., Benedict, C., Oral, H., Young, J. B., & Mann, D. L. (1996). Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). Journal of the American College of Cardiology, 27, 1201–1206.

    Article  CAS  Google Scholar 

  36. Vincenti, M. P., & Brinckerhoff, C. E. (2002). Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: Integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Research, 4, 157–164. Review.

    Google Scholar 

  37. Wang, S., Tan, D., Zhao, Y., Gao, G., Gao, X., & Hu, L. (1999). The effect of Pycnogenol on the microcirculation, platelet function and ischemic myocardium in patients with coronary artery disease. European Bulletin of Drug Research, 7, 19–25.

    CAS  Google Scholar 

  38. Wang, W. J., Viappiani, S., Sawicka, J., & Schulz, R. (2005). Inhibition of endogenous nitric oxide in the heart enhances matrix metalloproteinase-2 release. British Journal of Pharmacology, 145, 43–49.

    Article  PubMed  CAS  Google Scholar 

  39. Woodiwiss, A. J., Tsotetsi, O. J., Sprott, S., Lancaster, E. J., Mela, T., Chung, E. S., Meyer, T. E., & Norton, G. R. (2001). Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction. Circulation, 103, 155–160.

    PubMed  CAS  Google Scholar 

  40. Yang, B., Larson, D. F., Kelley, R., Beischel, J., & Watson, R. R. (2000). Conductivity: An issue for the application of the conductance catheter system in mice. Cardiovascular Engineering, 5, 57–60.

    Google Scholar 

  41. Yang, B., Larson, D. F., & Watson, R. (1999). Age-related left ventricular function in the mouse: Analysis based on in vivo pressure-volume relationships. American Journal of Physiology. Heart and Circulatory Physiology, 277, H1906–H1913.

    CAS  Google Scholar 

  42. Yu, Q., Larson, D. F., Slayback, D., Lundeen, T., Baxter, J. H., & Watson, R. R. (2004). Characterization of high salt and high fat diets on cardiac and vascular function in mice. Cardiovascular Toxicology, 4, 37–46.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Nutritional Sciences Department, The University of Arizona, Tucson, AZ, USA

    Sherma Zibadi & Ronald Ross Watson

  2. Sarver Heart Center, College of Medicine, The University of Arizona, Tucson, AZ, USA

    Qianli Yu, Douglas F. Larson & Ronald Ross Watson

  3. Institute of Pharmaceutical Chemistry, University of Münster, Münster, Germany

    Peter J. Rohdewald

  4. Division of Health Promotion Sciences, Mel and Enid Zuckerman Arizona College of Public Health, The University of Arizona, Tucson, AZ, 85724, USA

    Sherma Zibadi & Ronald Ross Watson

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  1. Sherma Zibadi
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Correspondence to Ronald Ross Watson.

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Zibadi, S., Yu, Q., Rohdewald, P.J. et al. Impact of Pycnogenol® on cardiac extracellular matrix remodeling induced by l-NAME administration to old mice. Cardiovasc Toxicol 7, 10–18 (2007). https://doi.org/10.1007/s12012-007-0001-9

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