Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein-kinin system in vascular endothelial cells

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Abstract

SUMMARY

Vascular farnesoid X receptor (FXR) ligands have been shown previously to regulate vascular tension. This study investigated whether FXR activation regulates vasoreactivity via the angiotensin II (Ang II) type 2 receptor (AT2R) and the kallikrein-kinin system in rat aortic vascular endothelial cells (RAECs). Protein abundances of Ang II type 1 receptor (AT1R), AT2R, bradykinin type 1/2 receptor (B1R, B2R), small heterodimer partner-1 (SHP-1) and the endothelial and inducible NO synthases (eNOS/iNOS) were analysed by Western blotting. Real-time quantitative polymerase chain reaction was performed to analyse expression of eNOS and iNOS mRNA. Kallikrein activity and bradykinin content were assayed using spectrophotometry and a bradykinin assay kit, respectively. Aortic vasoconstriction and vasodilation were also investigated following FXR activation in the presence or absence of AT2R and B2R blockade. It was found that the FXR agonists GW4064 and INT-747, in a dose-dependent manner, increased the protein abundance of AT2R, B2R and SHP-1 and decreased that of AT1R. AT2R blockade with PD123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP-1, B2R and bradykinin. Moreover, it was found that GW4064 and INT-747 upregulated expression of eNOS and enhanced NOS activity, which attenuated vasoconstriction and induced vasodilation, respectively. These effects were partially reversed by PD123319 and by B2R blockade with HOE140. The current work suggests that FXR regulates vascular tension by controlling the eNOS-NO system via activation of a pathway mediated by AT2R-B2R pathway in RAECs.

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