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All-Trans Retinoic Acid supplementation prevents cardiac fibrosis and cytokines induced by Methylglyoxal

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Abstract

Methylglyoxal (MG), a metabolic intermediate of glycolysis is a precursor for endogeneous production of advanced glycation end-products. The increased production of MG have negative influence over the structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic cardiac complications. Retinoic acid (RA), an active metabolite of vitamin A, has a major role in preventing cardiac remodeling and ventricular fibrosis. Hence, the objective of the present study was to determine whether rats administered with all-trans retinoic acid (RA) could attenuate MG induced pathological effects. Wistar rats were divided into 4 groups. Group 1 rats were kept as control; Group 2 rats were administrated with MG (75 mg/kg/day) for 8 weeks. Group 3 rats were given RA (Orally, 1.0 mg/kg/day) along with MG; Group 4 rats received RA alone. Cardiac antioxidant status, induction of fibrosis, AGE receptor (RAGE) and cytokines expression was evaluated in the heart tissues. Administration of MG led to depletion of antioxidant enzymes, induction of fibrosis (p < 0.001), up-regulated expression of RAGE (3.5 fold), TGF-β (4.4 fold), SMAD2 (3.7 fold), SMAD3 (6.0 fold), IL-6 (4.3 fold) and TNF-α (5.5 fold) in the heart tissues compared to control rats. Moreover, the exogenous administration of MG caused significant (p < 0.001) increase in the circulating CML levels. Whereas, RA treatment prevented the induction of fibrosis and restored the levels of cytokines and RAGE expression. Methylglyoxal-induced fibrosis can lead to pathological effects in the heart tissues. RA attenuates the effects of MG in the heart, suggesting that it can be of added value to usual diabetic therapy.

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Abbreviations

ALK4, ALK5:

Activin receptor-like kinase

CML:

Carboxy methyl lysine

GA:

Gallic acid

GAPDH:

Glyceraldehydes-3-phosphate dehydrogenase

GSH:

Glutathione

IL-1, IL-6:

Interleukin

TGF-β:

Transforming growth factor beta

TNF-α:

Tumor necrosis factor alpha

References

  1. Turk, Z.: Glycotoxines, carbonyl stress and relevance to diabetes and its complications. Physiol. Res. 59(2), 147–156 (2010)

    CAS  PubMed  Google Scholar 

  2. Rodrigues, T., Matafome, P., Santos-Silva, D., Sena, C., Seica, R.: Reduction of methylglyoxal-induced glycation by pyridoxamine improves adipose tissue microvascular lesions. J. Diabetes Res. 2013, 690650 (2013). doi:10.1155/2013/690650

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rabbani, N., Thornalley, P.J.: Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids 42(4), 1133–1142 (2012). doi:10.1007/s00726-010-0783-0

    Article  CAS  PubMed  Google Scholar 

  4. Price, C.L., Knight, S.C.: Advanced glycation: a novel outlook on atherosclerosis. Curr. Pharm. Des. 13(36), 3681–7 (2007). doi:10.2174/138161207783018608

    Article  CAS  PubMed  Google Scholar 

  5. Negre-Salvayre, A., Salvayre, R., Auge, N., Pamplona, R., Portero-Otin, M.: Hyperglycemia and glycation in diabetic complications. Antioxid. Redox Signal. 11(12), 3071–3109 (2009). doi:10.1089/ARS.2009.2484

    Article  CAS  PubMed  Google Scholar 

  6. Manolescu, D.C., Jankowski, M., Danalache, B.A., Wang, D., Broderick, T.L., Chiasson, J.L., Gutkowska, J.: All-trans retinoic acid stimulates gene expression of the cardioprotective natriuretic peptide system and prevents fibrosis and apoptosis in cardiomyocytes of obese ob/ob mice. Appl. Physiol. Nutr. Metab. 39(10), 1127–1136 (2014). doi:10.1139/apnm-2014-0005

    Article  CAS  PubMed  Google Scholar 

  7. Palm-Leis, A., Singh, U.S., Herbelin, B.S., Olsovsky, G.D., Baker, K.M., Pan, J.: Mitogen-activated protein kinases and mitogen-activated protein kinase phosphatases mediate the inhibitory effects of all-trans retinoic acid on the hypertrophic growth of cardiomyocytes. J. Biol. Chem. 279(52), 54905–54917 (2004). doi:10.1074/jbc.M407383200

    Article  CAS  PubMed  Google Scholar 

  8. Vistoli, G., De Maddis, D., Cipak, A., Zarkovic, N., Carini, M., Aldini, G.: Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic. Res. 47(Suppl 1), 3–27 (2013). doi:10.3109/10715762.2013.815348

    Article  CAS  PubMed  Google Scholar 

  9. Matafome, P., Sena, C., Seica, R.: Methylglyoxal, obesity, and diabetes. Endocrine 43(3), 472–484 (2013). doi:10.1007/s12020-012-9795-8

    Article  CAS  PubMed  Google Scholar 

  10. Ramasamy, R., Yan, S.F., Schmidt, A.M.: Advanced glycation endproducts: from precursors to RAGE: round and round we go. Amino Acids 42(4), 1151–1161 (2012). doi:10.1007/s00726-010-0773-2

    Article  CAS  PubMed  Google Scholar 

  11. Umadevi, S., Gopi, V., Elangovan, V.: Regulatory mechanism of gallic acid against advanced glycation end products induced cardiac remodeling in experimental rats. Chem. Biol. Interact. 208, 28–36 (2014). doi:10.1016/j.cbi.2013.11.013

    Article  CAS  PubMed  Google Scholar 

  12. Gkogkolou, P., Bohm, M.: Advanced glycation end products: key players in skin aging? Dermatoendocrinol. 4(3), 259–270 (2012). doi:10.4161/derm.22028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Giacco, F., Brownlee, M.: Oxidative stress and diabetic complications. Circ. Res. 107(9), 1058–1070 (2010). doi:10.1161/CIRCRESAHA.110.223545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Larson, R.S., Tallman, M.S.: Retinoic acid syndrome: manifestations, pathogenesis, and treatment. Best Pract. Res. Clin. Haematol. 16(3), 453–461 (2003)

    Article  CAS  PubMed  Google Scholar 

  15. Guo, X., Wang, X.F.: Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 19(1), 71–88 (2009). doi:10.1038/cr.2008.302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wrighton, K.H., Lin, X., Feng, X.H.: Phospho-control of TGF-beta superfamily signaling. Cell Res. 19(1), 8–20 (2009). doi:10.1038/cr.2008.327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Miyazawa, K., Shinozaki, M., Hara, T., Furuya, T., Miyazono, K.: Two major Smad pathways in TGF-β superfamily signalling. Genes Cell. 7(12), 1191–1204 (2002). doi:10.1046/j.1365-2443.2002.00599.x

    Article  CAS  Google Scholar 

  18. Ott, C., Jacobs, K., Haucke, E., Navarrete Santos, A., Grune, T., Simm, A.: Role of advanced glycation end products in cellular signaling. Redox Biol. 2, 411–429 (2014). doi:10.1016/j.redox.2013.12.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao, J., Randive, R., Stewart, J.A.: Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart. World J. Diabetes 5(6), 860–867 (2014). doi:10.4239/wjd.v5.i6.860

    Article  PubMed  PubMed Central  Google Scholar 

  20. Heo, Y.J., Oh, H.J., Jung, Y.O., Cho, M.L., Lee, S.Y., Yu, J.G., Park, M.K., Kim, H.R., Lee, S.H., Park, S.H., Kim, H.Y.: The expression of the receptor for advanced glycation end-products (RAGE) in RA-FLS is induced by IL-17 via Act-1. Arthritis Res. Ther. 13(4), R113 (2011). doi:10.1186/ar3398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Singh, V.P., Bali, A., Singh, N., Jaggi, A.S.: Advanced glycation end products and diabetic complications. Korean J. Physiol. Pharmacol. 18(1), 1–14 (2014). doi:10.4196/kjpp.2014.18.1.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology, School of Chemical & Biotechnology, SASTRA University, Thanjavur, 613 401, Tamil Nadu, India

    Umadevi Subramanian & Devipriya Nagarajan

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  1. Umadevi Subramanian
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  2. Devipriya Nagarajan
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Correspondence to Umadevi Subramanian.

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The authors declare no conflict of interest.

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Experimental procedures involving the use of animals or animal tissue were performed in accordance with the Indian National Law on animal care and use and approved by the Institutional Animal Ethics Committee at the SASTRA University.

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Subramanian, U., Nagarajan, D. All-Trans Retinoic Acid supplementation prevents cardiac fibrosis and cytokines induced by Methylglyoxal. Glycoconj J 34, 255–265 (2017). https://doi.org/10.1007/s10719-016-9760-5

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  • DOI: https://doi.org/10.1007/s10719-016-9760-5

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