Cardiovascular Research Advance Access first published online on October 13, 2008
This version [Corrected Proof] published online on November 6, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn279
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Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells
1 Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
2 Cardiovascular Research Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
3 Department of Metabolic Disorders, Amgen, Thousand Oaks, CA, USA
4 School of Biosciences, Cardiff University, Biomedical Sciences Building, Museum Avenue, Cardiff CF10 3US, UK
5 Faculty of Life Sciences, University of Manchester, Manchester, UK
6 Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK
* Corresponding authors. Tel: +44 292 087 9132; fax: +44 292 087 4116. E-mail address: riccardi{at}cardiff.ac.uk (D.R.). Tel: +44 161 275 5066; fax: +44 161 275 5082. E-mail address: ann.canfield{at}manchester.ac.uk (A.E.C.)
Aims: Vascular calcification (VC) is highly correlated with increased morbidity and mortality in advanced chronic kidney disease (CKD) patients. Allosteric modulation of the calcium-sensing receptor (CaR) by calcimimetics inhibits VC in animal models of advanced CKD. Here, we investigated the expression of the CaR in the vasculature and tested the ability of calcimimetics to prevent vascular smooth muscle cell (VSMC) calcification in vitro.
Methods and results: Immunohistochemical staining demonstrated that CaR protein is present in VSMC in normal, non-calcified human arteries. In contrast, low levels of CaR immunoreactivity were detected in atherosclerotic, calcified arteries. Immunfluorescence and immunoblotting revealed that CaR protein was also expressed by human and bovine VSMC in vitro. Acute stimulation of VSMC with increased Ca2+ stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, suggesting that the VSMC CaR is functional. VSMC CaR expression decreased when these cells deposited a mineralized matrix or following 24 h incubation in mineralization medium with increased (i.e. 1.8 or 2.5 mM) Ca2+. Culturing VSMC in mineralization medium containing 1.8 and 2.5 mM Ca2+ or with the membrane-impermeant CaR agonist Gd3+ enhanced mineral deposition compared with that observed in 1.2 mM Ca2+. Over-expression of dominant-negative (R185Q) CaR enhanced, whereas the calcimimetic R-568 attenuated, VSMC mineral deposition.
Conclusion: These results demonstrate that: (i) VSMCs express a functional CaR; (ii) a reduction in CaR expression is associated with increased mineralization in vivo and in vitro; (iii) calcimimetics decrease mineral deposition by VSMC. These data suggest that calcimimetics may inhibit the development of VC in CKD patients.
KEYWORDS Calcification; Extracellular calcium-sensing receptor, CaR; Vascular smooth muscle cells; Secondary hyperparathyroidism; Calcimimetics
Time for primary review: 33 days
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Cardiovasc Res 2009 81: 237-239.
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