Obiekt
Tytuł: The role of sphingosine kinase-1 in the pathophysiology of angiotensin II-induced arterial hypertension in mice
Abstrakt:
Sphingosine kinase 1 (Sphk1) is an enzyme responsible for the synthesis of sphingosine-1-phosphate (S1P), which acts through mechanisms dependent on specific membrane receptors (S1prs) or as an intracellular messenger and affects cardiovascular homeostasis. Imbalance in S1P synthesis and signaling may lead to the development of several cardiovascular pathologies including arterial hypertension. Depending on its localisation and induced signalling cascade, S1P acts as a vasoconstrictor or as a vasodilator, hence previous studies indicate an ambiguous role of Sphk1/S1P axis modulation in the development of arterial hypertension. However, several independent studies have clearly demonstrated that mice with global deletion of Sphk1 develop less severe hypertension in response to angiotensin II (AngII) infusion compared to wild type mice. The aim of this thesis was to investigate the effects of administration of a pharmacological selective Sphk1 inhibitor, PF543, on the development of hypertension and associated left ventricular hypertrophy, to assess therapeutic potential of this inhibitor. Studies revealed that chronic administration of PF543 significantly improves the vasodilatory capacity of mesenteric arteries in hypertensive mice. However, this improvement of endothelial function had no significant effect on systolic blood pressure level in mice. Studies also demonstrated th ; at PF543 administration partially protected against left ventricular hypertrophy in response to AngII treatment. PF543 significantly downregulated the expression of hypertrophy markers as examined by transcriptomic analysis, whereas histological analysis revealed that the inhibitor prevented cardiomyocyte enlargement, while it had no effect on cardiac fibrosis in hypertensive animals. The mechanism of PF543 action could be mediated by decreased S1pr1 expression, as well as by upregulated levels of S1P precursors, and this was accompanied by the inhibition of signaling pathways involving Rock1, PKC, Erk1/2 and Stat3. The thesis also aimed to assess the effects of siRNA-induced Sphk1 deficiency on the development of hypertrophy in mouse neonatal cardiomyocytes in vitro. Interestingly, downregulation of Sphk1 did not affect biological pathways related to the pathological type of hypertrophy, while it induced molecular pathways promoting final differentiation of cardiomyocytes at postnatal stage. Promotion of pathways characteristic for cardiomyocyte maturation was associated with the activation or upregulated expression of Akt and Mkk4 kinases, respectively. In summary, the studies described in this thesis found that PF543 inhibitor acted as an agent partially preventing cardiac hypertrophy and improving endothelial function in AngII-induced hypertension in mice. Additionally, th ; e studies revealed a heretofore unknown role of Sphk1 in the regulation of molecular pathways characteristic for postnatal cardiomyocyte maturation.
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Rada Dyscypliny Nauki medyczne
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Data ostatniej modyfikacji:
2 sty 2024
Data dodania obiektu:
14 lis 2023
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http://dl.cm-uj.krakow.pl:8080/publication/4990
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| Nazwa wydania | Data |
|---|---|
| ZB-137550 | 2 sty 2024 |
Obiekty
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Józefczuk, Ewelina
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