Systemic Delivery of aTransgene in Intact Animals by a Retroviral Vector

  • Michael J. Katovich
  • Hong-Wei Wang
  • Craig H. Gelband
  • Mohan K. Raizada
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 51)


Essential hypertension is a chronic cardiovascular disease that effects over 50 million people in the United States. It is a complex pathophysiological state that is primarily characterized by a sustained elevation in blood pressure (BP). If untreated, this chronically elevated BP can affect major target organs of the body including the heart, kidney, brain, and vascular system. As a consequence of the sustained high BP, there is an increased risk of mortality and morbidity that is characterized by myocardial infarction, congestive heart failure, stroke, end-stage renal failure, and peripheral vascular disease (1, 2, 3). Because hypertension is basically an asymptomatic disease, it confounds effective treatment and makes compliance a major issue in the treatment of this disease. Pharmacological agents currently utilized have to be administered daily in an attempt to control BP, and there are no agents available to cure essential hypertension. Thus, more effective therapeutic intervention is required in order to have a significant impact in alleviating this chronic disease and its lethal cardiovascular sequel.


Effective Therapeutic Intervention PA317 Cell G418 Resistant Coloni Virus Medium Direct Blood Pressure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Kang, P. M., Landau, A. J., Eberhardt, R. T., and Fishman, W. H. (1994) Angiotensin II receptor antagonists: a new approach to blockade of the renin angio-tensin system. Amer. Heart J. 127, 1388–1401.CrossRefPubMedGoogle Scholar
  2. 2.
    Whelton, P. K. (1994) Epidemiology of hypertension. Lancet 334, 101–106.CrossRefGoogle Scholar
  3. 3.
    Stamler, J., Stamler, R., and Neaton, J. D. (1993) Blood pressure, systolic and diastolic and cardiovascular risks: US population data. Arch. Intern. Med. 153, 598–615.CrossRefPubMedGoogle Scholar
  4. 4.
    Brunner, H. R., Nussberger, J., and Waeber, B. (1993) Angiotensin II blockade compared with other methods of inhibiting the renin-angiotensin system. J. Hypertens. 11, 553–558.Google Scholar
  5. 5.
    Parmley, W. W. (1998) Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection. Am. J. Med. 105, 27s–31s.CrossRefPubMedGoogle Scholar
  6. 6.
    Pitt, B. (1998) Regression of left ventricular hypertrophy in patients with hypertension: blockade of the renin-angiotensin-aldosterone system. Circulation 98, 1987–1989, 1998.PubMedGoogle Scholar
  7. 7.
    Jeunemaitre, X., Soubrier, F., Kotelevtsev, Y. V., Lifton, R. P., Williams, C. S., Charru, A., et al. (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell 71, 169–180.CrossRefPubMedGoogle Scholar
  8. 8.
    Vogt, M., Motz, W. H., Schwartzkopf, B., and Strauer, B. E., (1993) Pathophysiology and clinical aspects of hypertensive hypertrophy. Eur. Heart J. 14, 2–7.PubMedGoogle Scholar
  9. 9.
    Dzau, V. (1993) Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch. Intern. Med. 153, 937–942, 1993.CrossRefPubMedGoogle Scholar
  10. 10.
    Chao, J., Zhang, J. J., Lin, K. F., and Chao, L. (1998) Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats. Hum. Gene Ther. 9, 21–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Lin, K. F., Chao, J., and Chao, L. (1995) Human atrial natriuretic peptide gene delivery reduces blood pressure in hypertensive rats. Hypertension 26, 847–853.PubMedGoogle Scholar
  12. 12.
    Makino, N., Sugano, M., Ohtsuka, S., and Sawada, S. (1998) Intravenous injection with antisense oligonucleotides against angiotensinogen decreases blood pressure in spontaneously hypertensive rats. Hypertension 31, 1166–1170.PubMedGoogle Scholar
  13. 13.
    Phillips, M. I., Mahuczy-Dominiak, D., Coffey, M., Galli, S. M., Kimura, B., Wu, P., and Zelles, T. (1997) Prolonged reduction of high blood pressure with an in vivo, nonpathogenic, adeno-associated viral vector delivery of AT1R mRNA antisense. Hypertension 29, 374–380.PubMedGoogle Scholar
  14. 14.
    Tomita, N., Morishita, R., Higaki, J., Aoki, M., Nakamura, Y., Mikami, H., et al. (1995) Transient decrease in high blood pressure by in vivo transfer of antisense oligodeoxynucleotides against rat angiotensinogen. Hypertension 26, 131–136.PubMedGoogle Scholar
  15. 15.
    Iyer, S. N., Lu, D., Katovich, M. J., and Raizada, M. K. (1996) Chronic control of high blood pressure in the spontaneously hypertensive rat by delivery of angiotensin type 1 receptor antisense. Proc. Natl. Acad. Sci. USA 93, 9960–9965.CrossRefPubMedGoogle Scholar
  16. 16.
    Lu, D., Raizada, M. K., Iyer, S., Reaves, P., Yang, H., and Katovich, M. J. (1997) Losartan versus gene therapy: chronic control of high blood pressure in spontaneously hypertensive rats. Hypertension 30, 363–370.PubMedGoogle Scholar
  17. 17.
    Martens, J. R., Reaves, P. Y., Lu, D., Berecek, K. H., Bishop, S. P., Katovich, M. J., et al. (1998) Prevention of renovascular and cardiac pathophysiological changes in hypertension by angiotensin II type 1 receptor antisense gene therapy. Proc. Natl. Acad. Sci. USA 95, 2664–2669.CrossRefPubMedGoogle Scholar
  18. 18.
    Gelband, C. H., Reaves, P. Y., Evans, J., Wang, H., Katovich, M. J., and Raizada, M. K. (1999) Angiotensin II type 1 receptor antisense gene therapy prevents altered renal vascular calcium homeostasis in hypertension. Hypertension 33, 360–365.PubMedGoogle Scholar
  19. 19.
    Reaves, P. Y., Wang, H-W., Yang, H., Katovich, M. J., Berecek, K., and Raizada, M. K. (1999) Permanent prevention of hypertension by angiotensin type 1 receptor antisense gene therapy in the SHR. FASEB J. 13, A776.Google Scholar
  20. 20.
    Lu, D., Yu. K., and Raizada, M. K. (1995) Retrovirus-mediated transfer of an angiotensin type 1 receptor (AT1-R) antisense sequence decreases AT1RS and angiotensin action in astroglia and neuronal cells in primary culture. Proc. Natl. Acad. Sci. USA 92, 1162–1166.CrossRefPubMedGoogle Scholar
  21. 21.
    Ausubel, F. M., Brent, R., Kingston, R. E., Moore, D. D., Seidman, J. G., Smith, J. A., and Struhl, K. (1992) Short Protocols in Molecular Biology. Green Publishing Associates and Wiley, New York.Google Scholar
  22. 22.
    Raizada, M. K., Lu, D., Yang, H., Richards, M., Gelband, C. H., and Summers, C. (1999) Advances in Molecular and Cellular Endocrinology (Le Roith, D., ed.), vol. 3, JAI, Stamford, CT, pp. 75–101.Google Scholar
  23. 23.
    Lu, D. and Raizada, M. K. (1995) Delivery of angiotensin II type 1 receptor antisense inhibits angiotensin action in neurons from hypertensive rat brain. Proc. Natl. Acad. Sci. USA 92, 2914–2918.CrossRefPubMedGoogle Scholar
  24. 24.
    Iyer, S. N., Wright, B. E., Strubbe, G., Hanely, K., and Katovich, M. J. (1995) Chronic losartan treatment blocks isoproterenol-induced dipsogenesis. Physiol. Behav. 58, 283–286.CrossRefPubMedGoogle Scholar
  25. 25.
    Findlay, A. L. R., Fitzsimons, J. T., and Kucharczyk, J. (1979) Dependence of spontaneous and angiotensin-induced drinking in the rat upon the oestrous cycle and ovarian hormones. J. Endocrinol. 82, 215–225.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2001

Authors and Affiliations

  • Michael J. Katovich
    • 1
  • Hong-Wei Wang
    • 1
  • Craig H. Gelband
    • 1
  • Mohan K. Raizada
    • 1
  1. 1.Department of PharmacodynamicsUniversity of FloridaGainesville

Personalised recommendations