A2140 Antisense containing nanocomposites in hypertension treatment in ISIAH rats

Abstract

Objectives: Hypertension plays a central role in the development of severe complications, such as myocardial infarction and cerebral stroke. In this work, we studied the possibility of the treatment of hypertension by using TiO2∼PL-ODN-III and Si∼ODN-III nanocomposites containing conjugates of antisense oligonucleotides immobilized on TiO2 and Si nanoparticles. Methods: We used male hypertensive ISIAH (inherited stress-induced arterial hypertension) rats aged five months as a model of stress induced arterial hypertension. ISIAH rats were developed by long term selection for high blood pressure under emotional stress The inhibition of ACE1 was studied using the proposed nanocomposites using inhalation. Results: Inhalation of both modifications of oligonucleotides (TiO2∼PL-ODN-III & Si∼ODN-III) in a complex with nanoparticles led to a prolonged decrease in blood pressure in adult ISIAH rats. The maximal difference between the initial and minimal after inhalation BP levels was ∼30 mm Hg, and the average BP below the initial level by 22 mm Hg was maintained for two weeks in case of Si∼ODN-III usage. At the same time it was shown that inhalation of the nanocomposite bearing ODN against ACE1 significantly decreased expression of mRNA of the ACE1 gene in the lung tissue and ACE1 protein in the blood plasma. Conclusion: Development of methods for non-invasive application of antisense oligonucleotides in the composition with various nanocarriers opens new opportunities for the development of alternative methods of the struggle not only with hypertension, but also with other pathologies. The work was supported by the Russian Science Foundation, grant 16-15-10073