FXR-mediated regulation of angiotensin type 2 receptor expression in vascular smooth muscle cells.
OBJECTIVE
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. We and others have recently shown that FXR is also expressed in the vasculature, including endothelial cells and smooth muscle cells (SMC). However, the biological significance of FXR activation in SMC is still poorly understood. In this study, we examine the effect of FXR ligands on the angiotensin system in rat aortic SMC (RASMC), as angiotensin II (Ang II) signalling contributes to various types of vascular lesions by promoting cell growth of vascular SMC.


RESULTS
Treatment of RASMC with a FXR ligand showed no obvious effect on the expression of angiotensinogen, Ang II type 1 receptor (AT1R) or type 4 receptor (AT4R) but led to a significant increase in the expression of type 2 receptor (AT2R). FXR ligand treatment also resulted in an inhibition of Ang II-mediated extracellular signal-regulated kinase (ERK) activation and growth proliferation. Promoter reporter gene and electrophoretic mobility-shift assays suggest that FXR upregulates AT2R expression at a transcriptional level. Upregulation of AT2R appears to play a role in the FXR-mediated inhibition of ERK activation via upregulation of Rous sarcoma oncogene (Src) homology domain-containing tyrosine phosphatase 1 (SHP-1) because FXR-mediated upregulation of SHP-1 can be blocked by an AT2R antagonist and FXR-mediated ERK inactivation was significantly attenuated via treatment with either an AT2R antagonist or a SHP-1 inhibitor.


CONCLUSIONS
FXR in SMC may serve as a novel molecular target for modulating Ang II signalling in the vasculature.
Zhang
Qiuhong
Q
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 639 Salk Hall, Pittsburgh, PA 15261, USA.
He
Fengtian
F
Kuruba
Ramalinga
R
Gao
Xiang
X
Wilson
Annette
A
Li
Jiang
J
Billiar
Timothy R
TR
Pitt
Bruce R
BR
Xie
Wen
W
Li
Song
S
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D007555:Isoxazoles / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D000804:Angiotensin II; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D007555:Isoxazoles; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D044139:Receptor, Angiotensin, Type 2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C509250:Ptpn6 protein, rat; C412815:GW 4064