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Deoxycholic acid-modified polyethylenimine based nanocarriers for RAGE siRNA therapy in acute myocardial infarction

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Abstract

The activation of receptor for advanced glycation end products (RAGE) signaling is mainly associated with myocardial ischemia/reperfusion injury. Thus the blockade of RAGE-ligands axis can be considered as a potential therapeutic strategy to protect myocardial infarction after ischemia/reperfusion injury. Herein, we strengthened the cardioprotective effect with combinatorial treatment of soluble RAGE (sRAGE) and RAGE siRNA (siRAGE) causing more effective suppression of RAGE-mediated signaling transduction. For pharmacological blockade of RAGE, sRAGE, the extracellular ligand binding domain of RAGE, acts as a pharmacological ligand decoy and inhibits the interaction between RAGE and its ligands. For genetic deletion of RAGE, siRAGE suppresses the expression of RAGE by participating in RNA interference mechanism. Therefore, we combined these two RAGE blockade/deletion strategies and investigated the therapeutic effects on rat ischemic and reperfused myocardium. According to our results, based on RAGE expression level analysis and infarct size/fibrosis measurement, co-treatment of sRAGE and siRAGE exhibited synergic cardioprotective effects; thus the newly designed regimen can be considered as a promising candidate for the treatment of myocardial infarction.

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References

  • Abu-Amara, M., S.Y. Yang, N. Tapuria, B. Fuller, B. Davidson, and A. Seifalian. 2010. Liver ischemia/reperfusion injury: Processes in inflammatory networks—A review. Liver Transplantation 16: 1016–1032.

    Article  PubMed  Google Scholar 

  • Aleshin, A., R. Ananthakrishnan, Q. Li, R. Rosario, Y. Lu, W. Qu, F. Song, S. Bakr, M. Szabolcs, V. D’agati, R. Liu, S. Homma, A.M. Schmidt, S.F. Yan, and R. Ramasamy. 2008. RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model. American Journal of Physiology Heart and Circulatory Physiology 294: H1823–H1832.

    Article  CAS  PubMed  Google Scholar 

  • Andrassy, M., H.C. Volz, J.C. Igwe, B. Funke, S.N. Eichberger, Z. Kaya, S. Buss, F. Autschbach, S.T. Pleger, I.K. Lukic, F. Bea, S.E. Hardt, P.M. Humpert, M.E. Bianchi, H. Mairbäurl, P.P. Nawroth, A. Remppis, H.A. Katus, and A. Bierhaus. 2008. High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation 117: 3216–3226.

    Article  CAS  PubMed  Google Scholar 

  • Bucciarelli, L.G., R. Ananthakrishnan, Y.C. Hwang, M. Kaneko, F. Song, D.R. Sell, C. Strauch, V.M. Monnier, S.F. Yan, A.M. Schmidt, and R. Ramasamy. 2008. RAGE and modulation of ischemic injury in the diabetic myocardium. Diabetes 57: 1941–1951.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bucciarelli, L.G., M. Kaneko, R. Ananthakrishnan, E. Harja, L.K. Lee, Y.C. Hwang, S. Lerner, S. Bakr, Q. Li, Y. Lu, F. Song, W. Qu, T. Gomez, Y.S. Zou, S.F. Yan, A.M. Schmidt, and R. Ramasamy. 2006. Receptor for advanced-glycation end products: key modulator of myocardial ischemic injury. Circulation 113: 1226–1234.

    Article  CAS  PubMed  Google Scholar 

  • Chae, S.Y., H.J. Kim, M.S. Lee, Y.L. Jang, Y. Lee, S.H. Lee, K. Lee, S.H. Kim, H.T. Kim, S.C. Chi, T.G. Park, and J.H. Jeong. 2011. Energy-independent intracellular gene delivery mediated by polymeric biomimetics of cell-penetrating peptides. Macromolecular Bioscience 11: 1169–1174.

    Article  CAS  PubMed  Google Scholar 

  • Godbey, W.T., K.K. Wu, and A.G. Mikos. 1999. Size matters: Molecular weight affects the efficiency of poly(ethylenimine) as a gene delivery vehicle. Journal of Biomedical Materials Research 45: 268–275.

    Article  CAS  PubMed  Google Scholar 

  • Hofmann, M.A., S. Drury, C. Fu, W. Qu, A. Taguchi, Y. Lu, C. Avila, N. Kambham, A. Bierhaus, P. Nawroth, M.F. Neurath, T. Slattery, D. Beach, J. Mcclary, M. Nagashima, J. Morser, D. Stern, and A.M. Schmidt. 1999. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for s100/calgranulin polypeptides. Cell 97: 889–901.

    Article  CAS  PubMed  Google Scholar 

  • Kim, D., J. Hong, H.H. Moon, H.Y. Nam, H. Mok, J.H. Jeong, S.W. Kim, D. Choi, and S.H. Kim. 2013. Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia-reperfusion injury: use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier. Journal of Controlled Release 168: 125–134.

    Article  CAS  PubMed  Google Scholar 

  • Kim, H., S. Lim, H.-H. Moon, S. Kim, K.-C. Hwang, M. Lee, S. Kim, and D. Choi. 2010. Hypoxia-inducible vascular endothelial growth factor gene therapy using the oxygen-dependent degradation domain in myocardial ischemia. Pharmaceutical Research 27: 2075–2084.

    Article  CAS  PubMed  Google Scholar 

  • Lee, D., K.H. Lee, H. Park, S.H. Kim, T. Jin, S. Cho, J.H. Chung, S. Lim, and S. Park. 2013. The effect of soluble RAGE on inhibition of angiotensin II-mediated atherosclerosis in apolipoprotein E deficient Mice. PLoS ONE 8: e69669.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu, Q.L., G. Bou-Gharios, and T.A. Partridge. 2003. Non-viral gene delivery in skeletal muscle: a protein factory. Gene Therapy 10: 131–142.

    Article  CAS  PubMed  Google Scholar 

  • Meloche, J., A. Courchesne, M. Barrier, S. Carter, M. Bisserier, R. Paulin, J.F. Lauzon-Joset, S. Breuils-Bonnet, É. Tremblay, S. Biardel, C. Racine, C. Courture, P. Bonnet, S.M. Majka, Y. Deshaies, F. Picard, S. Provencher, and S. Bonnet. 2013. Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology. Journal of the American Heart Association 2: e005157.

    Article  PubMed Central  PubMed  Google Scholar 

  • Muhammad, S., W. Barakat, S. Stoyanov, S. Murikinati, H. Yang, K.J. Tracey, M. Bendszus, G. Rossetti, P.P. Nawroth, A. Bierhaus, and M. Schwaninger. 2008. The HMGB1 receptor RAGE mediates ischemic brain damage. Journal of Neuroscience 28: 12023–12031.

    Article  CAS  PubMed  Google Scholar 

  • Orlova, V.V., E.Y. Choi, C. Xie, E. Chavakis, A. Bierhaus, E. Ihanus, C.M. Ballantyne, C.G. Gahmberg, M.E. Bianchi, P.P. Nawroth, and T. Chavakis. 2007. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO Journal 26: 1129–1139.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ramasamy, R., S.J. Vannucci, S.S.D. Yan, K. Herold, S.F. Yan, and A.M. Schmidt. 2005. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15: 16R–28R.

    Article  CAS  PubMed  Google Scholar 

  • Ruponen, M., S. Rönkkö, P. Honkakoski, J. Pelkonen, M. Tammi, and A. Urtti. 2001. Extracellular glycosaminoglycans modify cellular trafficking of lipoplexes and polyplexes. Journal of Biological Chemistry 276: 33875–33880.

    Article  CAS  PubMed  Google Scholar 

  • Santilli, F., N. Vazzana, L.G. Bucciarelli, and G. Davì. 2009. Soluble forms of RAGE in human diseases: clinical and therapeutical implications. Current Medicinal Chemistry 16: 940–952.

    Article  CAS  PubMed  Google Scholar 

  • Xia, J.-R., N.-F. Liu, and N.-X. Zhu. 2008. Specific siRNA targeting the receptor for advanced glycation end products inhibits experimental hepatic fibrosis in rats. International Journal of Molecular Sciences 9: 638–661.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu, Y., F. Toure, W. Qu, L. Lin, F. Song, X. Shen, R. Rosario, J. Garcia, A.M. Schmidt, and S.-F. Yan. 2010. Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages. Journal of Biological Chemistry 285: 23233–23240.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yan, S.F., R. Ramasamy, and A.M. Schmidt. 2009. The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease. Expert Reviews in Molecular Medicine 11: e9.

    Article  PubMed Central  PubMed  Google Scholar 

  • Zeng, S., N. Feirt, M. Goldstein, J. Guarrera, N. Ippagunta, U. Ekong, H. Dun, Y. Lu, W. Qu, A.M. Schmidt, and J.C. Emond. 2004. Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice. Hepatology 39: 422–432.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was funded by Global Innovative Research Center (GiRC, 2012K1A1A2A01056095) program of National Research Foundation of Korea (NRF) and the Intramural Research Program of KIST (Global RNAi Carrier Initiative).

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Authors and Affiliations

  1. Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 136-791, South Korea

    Sook Hee Ku, Ji Hoon Jeong & Sun Hwa Kim

  2. Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, 120-752, South Korea

    Jueun Hong, Hyung-Ho Moon, Sungha Park & Donghoon Choi

  3. Korea Testing & Research Institute, Seoul, 150-039, South Korea

    Jueun Hong

  4. School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, South Korea

    Ji Hoon Jeong

  5. Department of Bioscience and Biotechnology, Konkuk University, Seoul, 143-701, South Korea

    Hyejung Mok

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  1. Sook Hee Ku
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  2. Jueun Hong
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  3. Hyung-Ho Moon
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  4. Ji Hoon Jeong
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  5. Hyejung Mok
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  6. Sungha Park
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  7. Donghoon Choi
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  8. Sun Hwa Kim
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Corresponding authors

Correspondence to Donghoon Choi or Sun Hwa Kim.

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Sook Hee Ku and Jueun Hong have contributed equally to this study.

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Ku, S.H., Hong, J., Moon, HH. et al. Deoxycholic acid-modified polyethylenimine based nanocarriers for RAGE siRNA therapy in acute myocardial infarction. Arch. Pharm. Res. 38, 1317–1324 (2015). https://doi.org/10.1007/s12272-014-0527-x

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  • DOI: https://doi.org/10.1007/s12272-014-0527-x

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