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Superoxide Dismutase – A Target for Gene Therapeutic Approach to Reduce Oxidative Stress in Erectile Dysfunction

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Free Radicals and Antioxidant Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 610))

Abstract

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. Oxidative stress has been demonstrated to be involved in the pathophysiology of age- or diabetes-related ED. Superoxide dismutase (SOD), an antioxidant enzyme catalyzing the conversion of superoxide anion (O2 •–) to hydrogen peroxide (H2O2) and molecular oxygen (O2), is a promising therapeutic target for ED. In vivo gene therapy and adult stem cell-based ex vivo gene therapy are two attractive current gene therapies for the treatment of ED. In this chapter we describe the use of two potent gene transfer techniques to deliver the therapeutic gene extracellular superoxide dismutase (ecSOD) into the penis of aged or diabetic rats for therapy of ED: adenoviral-mediated intracavernosal ecSOD gene transfer for gene therapy of ED and ecSOD gene-modified marrow stromal cells, also known as mesenchymal stem cells, based stem cell and gene therapy.

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References

  1. Consensus Conference., N.I.H. (1993) Impotence. NIH Consensus Development Panel on Impotence. JAMA 270, 83–90.

    Article  Google Scholar 

  2. Koskimaki, J., Hakkinen, J., Hakama, M., Huhtala, H., Tammela, T.L., and Shiri, R. (2005) Are questions on both achieving and maintaining an erection needed to define erectile dysfunction?. Int. J. Impot. Res. 17, 335–338.

    Article  CAS  PubMed  Google Scholar 

  3. Feldman, H.A., Goldstein, I., Hatzichristou, D.G., Krane, R.J., and McKinlay, J.B. (1994) Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J. Urol. 151, 54–61.

    CAS  PubMed  Google Scholar 

  4. Lewis, R.W. (2001) Epidemiology of erectile dysfunction. Urol. Clin. North. Am. 28, 209–216.

    Article  CAS  PubMed  Google Scholar 

  5. Seftel, A.D. (2003) Erectile dysfunction in the elderly: Epidemiology, etiology and approaches to treatment. J. Urol. 169, 1999–2007.

    Article  CAS  PubMed  Google Scholar 

  6. Shabsigh, R., Perelman, M.A., Lockhart, D.C., Lue, T.F., and Broderick, G.A. (2005) Health issues of men: Prevalence and correlates of erectile dysfunction. J. Urol. 174, 662–667.

    Article  CAS  PubMed  Google Scholar 

  7. Pommerville, P. (2003) Erectile dysfunction: An overview. Can. J. Urol. 10(Suppl 1), 2–6.

    PubMed  Google Scholar 

  8. Kinsey, A.C., Pomeroy, W.B., and Martin, C.E. (1948) Sexual Behavior in the Human Male, Philadelphia, WB Saunders Co.

    Google Scholar 

  9. McKinlay, J.B. (2000) The worldwide prevalence and epidemiology of erectile dysfunction. Int. J. Impot. Res. 12(Suppl 4), S6–S11.

    Article  PubMed  Google Scholar 

  10. Cappelleri, J.C. and Rosen, R.C. (2005) The Sexual Health Inventory for Men (SHIM): A 5-year review of research and clinical experience. Int. J. Impot. Res. 17, 307–319.

    Article  CAS  PubMed  Google Scholar 

  11. Shabsigh, R. and Anastasiadis, A.G. (2003) Erectile dysfunction. Annu. Rev. Med. 54, 153–168.

    Article  CAS  PubMed  Google Scholar 

  12. Burnett, A.L., Lowenstein, C.J., Bredt, D.S., Chang, T.S.K., and Snyder, S.H. (1992) Nitric oxide: Physiologic mediator of penile erection. Science 257, 401–403.

    Article  CAS  PubMed  Google Scholar 

  13. Rajfer, J., Aronson, W.J., Bush, P.A., Dorey, F.J., and Ignarro, L.J. (1992) Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N. Engl. J. Med. 326, 90–94.

    Article  CAS  PubMed  Google Scholar 

  14. Jeremy, J.Y., Angelini, G.D., Khan, M., Mikhailidis, D.P., Morgan, R.J., Thompson, C.S., Bruckdorfer, K.R., and Naseem, K.M. (2000) Platelets, oxidant stress and erectile dysfunction: An hypothesis. Cardiovasc. Res. 46, 50–54.

    Article  CAS  PubMed  Google Scholar 

  15. Jones, R.W., Rees, R.W., Minhas, S., Ralph, D., Persad, R.A., and Jeremy, J.Y. (2002) Oxygen free radicals and the penis. Expert Opin. Pharmacother. 3, 889–897.

    Article  CAS  PubMed  Google Scholar 

  16. Azadzoi, K.M., Schulman, R.N., Aviram, M., and Siroky, M.B. (2005) Oxidative stress in arteriogenic erectile dysfunction: Prophylactic role of antioxidants. J. Urol. 174, 386–393.

    Article  CAS  PubMed  Google Scholar 

  17. Bivalacqua, T.J., Armstrong, J.S., Biggerstaff, J., Abdel-Mageed, A.B., Kadowitz, P.J., Hellstrom, W.J., and Champion, H.C. (2003) Gene transfer of extracellular SOD to the penis reduces O2 •– and improves erectile function in aged rats. Am. J. Physiol. Heart Circ. Physiol. 284, H1408–H1421.

    CAS  PubMed  Google Scholar 

  18. Bivalacqua, T.J., Usta, M.F., Kendirci, M., Pradhan, L., Alvarez, X., Champion, H.C., Kadowitz, P.J., and Hellstrom, W.J. (2005) Superoxide anion production in the rat penis impairs erectile function in diabetes: Influence of in vivo extracellular superoxide dismutase gene therapy. J. Sex. Med. 2, 187–197, Discussion 197–198.

    Article  CAS  PubMed  Google Scholar 

  19. Gryglewski, R.J., Palmer, R.M., and Moncada, S. (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320, 454–456.

    Article  CAS  PubMed  Google Scholar 

  20. Fukai, T., Folz, R.J., Landmesser, U., and Harrison, D.G. (2002) Extracellular superoxide dismutase and cardiovascular disease. Cardiovasc. Res. 55, 239–249.

    Article  CAS  PubMed  Google Scholar 

  21. Squadrito, G.L. and Pryor, W.A. (1998) Oxidative chemistry of nitric oxide: The roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic. Biol. Med. 25, 392–403.

    Article  CAS  PubMed  Google Scholar 

  22. Stralin, P., Karlsson, K., Johansson, B.O., and Marklund, S.L. (1995) The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler. Thromb. Vasc. Biol. 15, 2032–2036.

    CAS  PubMed  Google Scholar 

  23. Marklund, S.L. (1982) Human copper-containing superoxide dismutase of high molecular weight. Proc. Natl. Acad. Sci. USA 79, 7634–7638.

    Article  CAS  PubMed  Google Scholar 

  24. Levin, E.D. (2005) Extracellular superoxide dismutase (EC-SOD) quenches free radicals and attenuates age-related cognitive decline: Opportunities for novel drug development in aging. Curr. Alzheimer Res. 2, 191–196.

    Article  CAS  PubMed  Google Scholar 

  25. Davidson, B.L., Allen, E.D., Kozarsky, K.F., Wilson, J.M., and Roessler, B.J. (1993) A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nat. Genet. 3, 219–223.

    Article  CAS  PubMed  Google Scholar 

  26. Champion, H.C., Bivalacqua, T.J., D’Souza, F.M., Ortiz, L.A., Jeter, J.R., Toyoda, K., Heistad, D.D., Hyman, A.L., and Kadowitz, P.J. (1999) Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses. Circ. Res. 84, 1422–1432.

    CAS  PubMed  Google Scholar 

  27. Gunnett, C.A., Lund, D.D., Chu, Y., Brooks, R.M., 2nd., Faraci, F.M., and Heistad, D.D. (2001) NO-dependent vasorelaxation is impaired after gene transfer of inducible NO-synthase. Arterioscler. Thromb. Vasc. Biol. 21, 1281–1287.

    Article  CAS  PubMed  Google Scholar 

  28. Chu, Y., Iida, S., Lund, D.D., Weiss, R.M., DiBona, G.F., Watanabe, Y., Faraci, F.M., and Heistad, D.D. (2003) Gene transfer of extracellular superoxide dismutase reduces arterial pressure in spontaneously hypertensive rats: Role of heparin-binding domain. Circ. Res. 92, 461–468.

    Article  CAS  PubMed  Google Scholar 

  29. Bivalacqua, T.J., Champion, H.C., Usta, M.F., Cellek, S., Chitaley, K., Webb, R.C., Lewis, R.L., Mills, T.M., Hellstrom, W.J., and Kadowitz, P.J. (2004) RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: A mechanism for diabetes-associated erectile dysfunction. Proc. Natl. Acad. Sci. USA 101, 9121–9126.

    Article  CAS  PubMed  Google Scholar 

  30. Bivalacqua, T.J., Usta, M.F., Champion, H.C., Leungwattanakij, S., Dabisch, P.A., McNamara, D.B., Kadowitz, P.J., and Hellstrom, W.J. (2004) Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int. J. Impot. Res. 16, 21–29.

    Article  CAS  PubMed  Google Scholar 

  31. Deng, W., Bivalacqua, T.J., Chattergoon, N.N., Hyman, A.L., Jeter, J.R., Jr., and Kadowitz, P.J. (2003) Adenoviral gene transfer of endothelial nitric oxide synthase: High level expression in ex vivo expanded marrow stromal cells. Am. J. Physiol. Cell Physiol. 285, C1322–C1329.

    CAS  PubMed  Google Scholar 

  32. Deng, W., Bivalacqua, T.J., Chattergoon, N.N., Jeter, J.R., Jr., and Kadowitz, P.J. (2004) Engineering ex vivo-expanded marrow stromal cells to secrete calcitonin gene-related peptide using adenoviral vector. Stem Cells 22, 1279–1291.

    Article  CAS  PubMed  Google Scholar 

  33. Deng, W., St Hilaire, R.C., Chattergoon, N.N., Jeter, J.R., Jr., and Kadowitz, P.J. (2006) Inhibition of vascular smooth muscle cell proliferation in vitro by genetically engineered marrow stromal cells secreting calcitonin gene-related peptide. Life Sci. 78, 1830–1838.

    Article  CAS  PubMed  Google Scholar 

  34. Christ, G.J., Rehman, J., Day, N., Salkoff, L., Valcic, M., Melman, A., and Geliebter, J. (1998) Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am. J. Physiol. 275, H600–H608.

    CAS  PubMed  Google Scholar 

  35. Bivalacqua, T.J., Deng, W., Kendirci, M., Usta, M.F., Robinson, C., Taylor, B.K., Murthy, S.N., Champion, H.C., Hellstrom, W., and Kadowitz, P.J. (2007) Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction. Am. J. Physiol. Heart Circ. Physiol. 292, H1278–H1290.

    Article  CAS  PubMed  Google Scholar 

  36. Greuenewald, D.A., Naai, M.A., Hess, D.L., and Matsumoto, A.M. (1994) The brown Norway rat as a model of reproductive aging: Evidence for both primary and secondary testicular failure. J. Gerontol. B Psychol. Sci. Soc. Sci. 49, B42–B50.

    Google Scholar 

  37. Rajasekaran, M., Kasyan, A., Jain, A., Kim, S.W., and Monga, M. (2002) Altered growth factor expression in the aging penis: The Brown-Norway rat model. J. Androl. 23, 393–399.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Drs. Beverley Davidson, Yi Chu, and Donald D. Heistad and the University of Iowa Gene Transfer Vector Core for the preparation of adenoviral vectors. Studies presented in this chapter are supported in part by NIH grant HL62000.

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Deng, W., Bivalacqua, T., Champion, H., Hellstrom, W., Murthy, S.N., Kadowitz, P.J. (2010). Superoxide Dismutase – A Target for Gene Therapeutic Approach to Reduce Oxidative Stress in Erectile Dysfunction. In: Uppu, R., Murthy, S., Pryor, W., Parinandi, N. (eds) Free Radicals and Antioxidant Protocols. Methods in Molecular Biology, vol 610. Humana Press. https://doi.org/10.1007/978-1-60327-029-8_13

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  • DOI: https://doi.org/10.1007/978-1-60327-029-8_13

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