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Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein‐kinin system in vascular endothelial cells
Author(s) -
Zhang Ran,
Ran Haihong,
Peng Liang,
Zhang Ying,
Shen Wenbin,
Sun Ting,
Cao Feng,
Chen Yundai
Publication year - 2016
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12535
Subject(s) - bradykinin , farnesoid x receptor , endocrinology , chemistry , medicine , enos , vasodilation , angiotensin ii , receptor , kallikrein , vasoconstriction , biology , nitric oxide synthase , nitric oxide , biochemistry , nuclear receptor , enzyme , transcription factor , gene
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 ( AT 2 R) and the kallikrein‐kinin system in rat aortic vascular endothelial cells ( RAEC s). Protein abundances of Ang II type 1 receptor ( AT 1 R), AT 2 R, bradykinin type 1/2 receptor (B 1 R, B 2 R), 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 AT 2 R and B 2 R blockade. It was found that the FXR agonists GW 4064 and INT ‐747, in a dose‐dependent manner, increased the protein abundance of AT 2 R, B 2 R and SHP ‐1 and decreased that of AT 1 R. AT 2 R blockade with PD 123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP ‐1, B 2 R and bradykinin. Moreover, it was found that GW 4064 and INT ‐747 upregulated expression of eNOS and enhanced NOS activity, which attenuated vasoconstriction and induced vasodilation, respectively. These effects were partially reversed by PD 123319 and by B 2 R blockade with HOE 140. The current work suggests that FXR regulates vascular tension by controlling the eNOS ‐ NO system via activation of a pathway mediated by AT 2 R‐B 2 R pathway in RAECs.