FXR-mediated regulation of angiotensin type 2 receptor expression in vascular smooth muscle cells

Qiuhong Zhang, Fengtian He, Ramalinga Kuruba, Xiang Gao, Annette Wilson, Jiang Li, Timothy R. Billiar, Bruce R. Pitt, Wen Xie, Song Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)560-569
Number of pages10
JournalCardiovascular Research
Volume77
Issue number3
DOIs
StatePublished - Feb 2008
Externally publishedYes

Keywords

  • Angiotensin II
  • Angiotensin II type 2 receptor
  • FXR
  • Regulation
  • Smooth muscle cells

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