Skip to main content
Log in

Toward gene therapy of hypertension: Experimental study on hypertensive ISIAH rats

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

TiO2-based nanocomposites were prepared to deliver oligonucleotides into cells. The nanocomposites were designed by the immobilization of polylysine-containing oligonucleotides on TiO2-nanoparticles (TiO2·PL-DNA). We showed for the first time the possibility of using the proposed nanocomposites for treatment of hypertensive disease by introducing them into hypertensive ISIAH rats developed as a model of stress-sensitive arterial hypertension. The mRNA of the gene encoding angiotensin I-converting enzyme (ACE1) involved in the synthesis of angiotensin II was chosen as a target. Administration (intraperitoneal injection and inhalation) of the nanocomposite showed a significant (by 20-30 mm Hg) decrease in systolic blood pressure when the nanocomposite contained the ACE1 gene-targeted oligonucleotide. When using the oligonucleotide with a random sequence, no effect was observed. Further development and improvement of the inhalation nanocomposite drug delivery to systemic hypertensive disease treatment promises new possibilities for clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ACE1:

angiotensin I-converting enzyme

BP:

arterial blood pressure

ISIAH:

inherited stress-induced arterial hypertension

NA:

nucleic acid

TiO2·PL-DNA:

nanocomposites designed by the immobilization of polylysine-containing oligonucleotides on TiO2-nanoparticles

References

  1. Kumar, J. (2013) Epidemiology of hypertension, Clin. Queries Nephrol., 2, 56–61.

    Article  Google Scholar 

  2. Chobanian, A. V., Bakris, G. L., Black, H. R., Cushman, W. C., Green, L. A., Izzo, J. L., Jones, D. W., Materson B. J., Oparil, S., Wright, J. T., and Roccella, E. J. (2003) The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report, JAMA, 289, 2560–2572.

    Article  CAS  PubMed  Google Scholar 

  3. Levina, A., Ismagilov, Z., Repkova, M., Shatskaya, N., Shikina, N., Tusikov, F., and Zarytova, V. (2012) Nanocomposites consisting of titanium dioxide nanoparticles and oligonucleotides, J. Nanosci. Nanotechnol., 12, 1812–1820.

    Article  CAS  PubMed  Google Scholar 

  4. Levina, A. S., Mikhaleva, E. A., Repkova, M. N., and Zarytova, V. F. (2008) Synthesis of polyamine-containing oligonucleotides, Bioorg. Khim., 34, 89–95.

    CAS  PubMed  Google Scholar 

  5. Levina, A. S., Ismagilov, Z. R., Repkova, M. N., Shikina, N. V., Baiborodin, S. I., Shatskaya, N. V., Zagrebelniy, S. N., and Zarytova, V. F. (2013) The creation of TiO2~DNAnanocomposites, able to enter the cells, Bioorg. Khim., 39, 87–98.

    CAS  Google Scholar 

  6. Markel, A. L. (1992) Development of a new strain of rats with inherited stress-induced arterial hypertension, in: Genetic Hypertension Colloque INSERM (Sassard, J., ed.) Vol. 218, John Libbey Eurotext Ltd., London, pp. 405–407.

    Google Scholar 

  7. Markel, A. L., Maslova, L. N., Shishkina, G. T., Mahanova, N. A., and Jacobson, G. S. (1999) Developmental influences on blood pressure regulation in ISIAH rats, in: Development of the Hypertensive Phenotype, Basic and Clinical Studies. In the series Handbook of Hypertension (McCarty, R., Blizard, D. A., and Chevalier, R. L., eds.) Elsevier, Amsterdam, pp. 93–526.

    Google Scholar 

  8. Phillips, M. I. (2001) Gene therapy for hypertension: the preclinical data, Hypertension, 38, 543–548.

    Article  CAS  PubMed  Google Scholar 

  9. Daya, S., and Berns, K. I. (2008) Gene therapy using adenoassociated virus vectors, Clin. Microbiol. Rev., 21, 583–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cataliotti, A., Tonne, J. M., Bellavia, D., Martin, F. L., Oehler, E. A., Harders, G. E., Campbell, J. M., Peng, K.W., Russell, S. J., Malatino, L. S., Burnett, J. C., and Ikeda, Y. (2011) Long-term cardiac pro-B-type natriuretic peptide gene delivery prevents the development of hypertensive heart disease in spontaneously hypertensive rats, Circulation, 123, 1297–1305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aguero, J., Ishikawa, K., Hadri, L., Santos-Gallego, C. G., Fish, K. M., Kohlbrenner, E., Hammoudi, N., Kho, C., Lee, A., Ibanez, B., Garcia-Alvarez, A., Zsebo, K., Maron, B. A., Plataki, M., Fuster, V., Leopold, J. A., and Hajjar, R. J. (2016) Intratracheal gene delivery of SERCA2a ameliorates chronic post-capillary pulmonary hypertension. A large animal model, J. Am. Coll. Cardiol., 67, 2032–2046.

    Article  CAS  PubMed  Google Scholar 

  12. Turnbull, I. C., Eltoukhy, A. A., Fish, K. M., Nonnenmacher, M., Ishikawa, K., Chen, J., Hajjar, R. J., Anderson, D. G., and Costa, K. D. (2016) Myocardial delivery of lipidoid nanoparticle carrying modRNA induces rapid and transient expression, Mol. Ther., 24, 66–75.

    Article  CAS  PubMed  Google Scholar 

  13. Juliano, R. L., Ming, X., and Nakagawa, O. (2012) Cellular uptake and intracellular trafficking of antisense and siRNA oligonucleotides, Bioconjug. Chem., 23, 147–157.

    Article  CAS  PubMed  Google Scholar 

  14. Petros, R. A., and DeSimone, J. M. (2010) Strategies in the design of nanoparticles for therapeutic applications, Nat. Rev. Drug Discov., 9, 615–627.

    Article  CAS  PubMed  Google Scholar 

  15. Levina, A., Repkova, M. N., Ismagilov, Z. R., Shikina, N. V., Malygin, E. G., Mazurkova, N. A., Zinov’ev, V. V., Evdokimov, A., Baiborodin, S. I., and Zarytova, V. F. (2012) High-performance method for specific effect on nucleic acids in cells using TiO2~DNA nanocomposites, Sci. Rep., 2, 756.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Levina, A. S., Repkova, M. N., Mazurkova, N. A., Makarevich, E. V., Ismagilov, Z. R., and Zarytova, V. F. (2015) Knockdown of different influenza A virus subtypes in cell culture by a single antisense oligodeoxyribonucleotide, Int. J. Antimicrob. Agents, 46, 125–128.

    Article  CAS  PubMed  Google Scholar 

  17. Levina, A. S., Repkova, M. N., Bessudnova, E. V., Filippova, E. I., Mazurkova, N. A., and Zarytova, V. F. (2016) High antiviral effect of DNA fragments in TiO2·PLDNA nanocomposites targeted to conservative regions of (–)RNA and (+)RNA of influenza A virus, Beilstein J. Nanotechnol., 7, 1166–1173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dubinina, A. D., Nizomov, S. A., Markel, A. L., and Ivanova, L. N. (2016) The reaction of the kidney in rats with stress-induced hypertension (ISIAH line) on the osmotic load of sodium chloride, Ros. Fiziol. Zh., 102, 56–66.

    CAS  Google Scholar 

  19. Antonov, Y. V., Alexandrovich, Y. V., Redina, O. E., Gilinsky, M. A., and Markel, A. L. (2016) Stress and hypertensive disease: adrenals as a link. Experimental study on hypertensive ISIAH rat strain, Clin. Exp. Hypertens., 38, 415–423.

    Article  CAS  PubMed  Google Scholar 

  20. Fedoseeva, L. A., Ryazanova, M. A., Ershov, N. I., Markel, A. L., and Redina, O. E. (2016) Comparative transcriptional profiling of renal cortex in rats with inherited stressinduced arterial hypertension and normotensive Wistar Albino Glaxo rats, BMC Genet., 17, S1:12, 5–18.

    Article  Google Scholar 

  21. Redina, O. E., Smolenskaya, S. E., Maslova, L. N., and Markel, A. L. (2013) The genetic control of blood pressure and body composition in rats with stress-sensitive hypertension, Clin. Exp. Hypertens., 35, 484–495.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. L. Markel.

Additional information

Published in Russian in Biokhimiya, 2017, Vol. 82, No. 4, pp. 620-625.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM16-314, December 5, 2016.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Repkova, M.N., Levina, A.S., Seryapina, A.A. et al. Toward gene therapy of hypertension: Experimental study on hypertensive ISIAH rats. Biochemistry Moscow 82, 454–457 (2017). https://doi.org/10.1134/S000629791704006X

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S000629791704006X

Keywords

Navigation