Goncharov S. Molecular genetic mechanisms of proteasomal proteolysis disorder in arterial hypertension and approaches to its correction

The dissertation is devoted to the research on the role of proteasomal proteolysis in arterial hypertension. The research was performed among a group of children and adolescents with primary hypertension and healthy children as well. We have determined gene polymorphisms that encode proteasome subunits (LMP2 Arg60His, LMP7 Lys145Gln and PSMA6 C–8G). The obtained data indicate that the distribution of allelic variants of genes, that encode the immunoproteasome (LMP2) and proteasome (PSMA6) subunit, significantly differs between the control group and the group of children with arterial hypertension in contradistinction with the LMP7 gene polymorphism. Subsequently, the research has been performed on spontaneously hypertensive rats (SHR) with the quercetin correction (tablet form, 15 mg per kg of body weight, daily). Comparison of morphological, histological, cardiohemodynamic, and morphometric parameters of the aorta and heart of SHR with Wistar rats suggests that a chronic increase of high blood pressure leads to significant disorders. Thus, SHR had the following parameters decreased: stroke volume (3 times), ejection fraction (2.14 times), stroke work (70%), heart rate (12%), minimum pressure (1.5 times), and end-systolic pressure (15%). Diastolic heart function parameters in SHR were higher: end-diastolic blood pressure 6.5 times, dp/dt min 30%, and arterial elastance 4.4 times. Significant morphological changes of the aorta were detected in SHR. The following parameters were increased: aorta total width (by 36%), smooth muscle cell width (by 19%), and intima width (1.9 times). The efficiency of experimental therapy of arterial hypertension with the use of a proteasome inhibitor - quercetin has been proved. Bioflavonoids could prevent the increase of the following parameters: aortic wall lipidosis of SHR (2 times) and the percentage of left ventricle fibrotic changes (2.9 times). A statistically significant decrease was observed in the expression level of the following genes in the aortic tissues of SHR: PSMB2 (28 times), PSMB8 (5.5 times), PSMB9 (112 times), and PSME1 (7.8 times). In contrast, the mRNA level of the PSMB1 gene was 7.8 times higher.