Cardiovascular Research Advance Access originally published online on November 13, 2007
Cardiovascular Research 2008 77(3):560-569; doi:10.1093/cvr/cvm068
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FXR-mediated regulation of angiotensin type 2 receptor expression in vascular smooth muscle cells
1 Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 639 Salk Hall, Pittsburgh, PA 15261, USA
2 Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
3 Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
* Corresponding author. Tel: +1 412 383 7976; fax: +1 412 648 1664. E-mail address: sol4{at}pitt.edu
Aims: 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.
Methods and 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.
Conclusion: FXR in SMC may serve as a novel molecular target for modulating Ang II signalling in the vasculature.
KEYWORDS FXR; Angiotensin II; Angiotensin II type 2 receptor; Smooth muscle cells; Regulation
Time for primary review: 20 days
Equal contribution to this work.