Mezhenskyi O. Role of PPAR-gamma in regulation of endothelium-dependent reactions of rat aorta in norm and in type 2 diabetes.

The thesis is dedicated to the study of endothelium-dependent relaxation of thoracic rat aorta, how PPAR regulates this process, how components of endothelium-dependent relaxation change under type 2 diabetes, to non-specific effects of PPAR ligands, and to spatial differences in endothelium-dependent reactions in proximal and distal regions of rat aorta. During the study, the next methods were used: tensitometry, molecular docking, RNAsequencing, and experimental model of type 2 diabetes. In this study, we have been the first who show differential expression gradient and functional gradient for potassium inward rectifying channels, L-type calcium channels, tubulin, and muscular complex elements between proximal and distal parts of the thoracic aorta. It facilitates our understanding of intricate regulations of rat aorta and allows researchers to better control variation in experimental data regarding aorta reactions in their studies. Investment of endothelium-dependent hyperpolarizing factor (EDHF), nitric oxide (NO), TRPV4 channel, prostanoids, and nonadrenergic noncholinergic neuromediators in endothelium-dependent relaxation in norm was shown. Also, we have shown the ratio of investment of calcium-dependent potassium channels' small and intermediate conductance in TRPV4-dependent relaxation. It was shown that agonist PPAR-γ — rosiglitazone effects are connected to impact on NO, prostanoids, and TRPV4 increasing their impact, but not on EDHF. In addition, it was shown for the first time that the rosiglitazone effect is connected to the direct impact on 8 soluble guanylate cyclase, which can explain the observed effects of PPAR ligands on the cardiovascular system, which was shown in previous studies. A study of endothelium-dependent relaxation components contributions in diabetes showed that EDHF contribution significantly decreased, and the contribution of NO and prostanoids increased. Also, we have shown that TRPV4-dependent relaxation is amplified in type 2 diabetes and the contribution of calcium-dependent potassium channels' small conductance increases. The application of rosiglitazone in diabetes, the same as in control, amplifies the effects of NO, prostanoids, and TRPV4. Using molecular docking we was the first who have shown abilities of rosiglitazone to non-specifically binding to two pore domain potassium channels TWIK and TRAAK, and also with soluble guanylat cyclase, what may be used in next pharmacological studies.