title: Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein-kinin system in vascular endothelial cells.
abstract: 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 (AT2 R) and the kallikrein-kinin system in rat aortic vascular endothelial cells (RAECs). Protein abundances of Ang II type 1 receptor (AT1 R), AT2 R, bradykinin type 1/2 receptor (B1 R, B2 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 AT2 R and B2 R blockade. It was found that the FXR agonists GW4064 and INT-747, in a dose-dependent manner, increased the protein abundance of AT2 R, B2 R and SHP-1 and decreased that of AT1 R. AT2 R blockade with PD123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP-1, B2 R 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 B2 R 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 AT2 R-B2 R pathway in RAECs.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Geriatric Haematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Ran
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016234:Kallikrein-Kinin System / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D065094:Bradykinin B2 Receptor Antagonists; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C509250:Ptpn6 protein, rat
keywords: angiotensin II type 2 receptor; bradykinin type 2 receptor; farnesoid X receptor; vascular tension