Endocrine Abstracts

Glucocorticoids are known to have significant and diverse effects on the cardiovascular system. They have been shown to foster hypertension indirectly due to enhanced vascular tone by potentiation of the vasocontrictor hormones and directly by action on vascular smooth muscle cells (VSMC). The local concentration of glucocorticoids in various tissue including vessels is determined by the enzyme 11β-hydroxysteroid dehydrogenase type two (11HSD2) and 1 (11HSD1) that has been shown to be down-regulated by PPARγ agonists in hepatocytes and adipocytes. Thus it can be hypothesized that PPARγ activation is able to induce a vasodepressor effect. However, PPARγ knock-out mice and animals with VSMC-selective PPARγ deficiency have hypotension. Therefore, in the present study the effect of PPARγ agonist pioglitazone on 11HSDs expression was assessed in primary cultures of VSMC derived form rat aorta. Pioglitazone significantly increased 11HSD1 activity (11-reductase) and mRNA expression in a dose-dependent manner with EC50 243 nM and this effect was not blocked by RU 486, an antagonist of the glucocorticoid receptor. Corticosterone had no effect on 11HSD1 expression. Pioglitazone positively regulated transcription of two CCAAT/enhancer-binding proteins (C/EBPs), specifically C/EBPα a potent activator of 11HSD1 gene transcription in some cells types, and C/EBPζ, whereas C/EBPβ and C/EBPδ were not changed. In contrast, corticosterone stimulated the expression of C/EBPβ and C/EBPδ, but the levels of C/EBPα and C/EBPζ were not changed. 11β-oxidase activity was not detected in VSMC in either control or pioglitazone treated cells even if weak signal for 11HSD2 mRNA expression was found. In conclusion, activation of PPARγ in VSMC up-regulates vascular 11HSD1 and thus reactivates 11-oxo metabolites to biologically active glucocorticoids through a mechanism that seems to involve C/EBPα and C/EBPζ. Our data provide one of the possible explanations for PPARγ agonists’ effects on the cardiovascular system.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.