Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 13, 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
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* Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, UK
Cardiovascular Research Group, Faculty of Medical & Human Sciences, University of Manchester, UK
Department of Metabolic Disorders, Amgen, Thousand Oaks, CA, USA
School of Biosciences, Cardiff University, UK
Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, UK
Correspondence: Dr Riccardi, Biomedical Sciences Building, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK (Tel: +44(0)2920879132; FAX: +44(0)2920874116; e-mail: riccardi{at}cardiff.ac.uk) or Dr Canfield, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK (Tel: +44(0)1612755066; FAX: +44(0)1612755082; e-mail: ann.canfield{at}manchester.ac.uk)
Aims: Vascular calcification (VC) is highly correlated with increased morbidity and mortality in advanced chronic kidney disease patients. Allosteric modulation of the calcium-sensing receptor (CaR) by calcimimetics inhibits VC in animal models of advanced chronic kidney disease. 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-hour 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-impermeable CaR agonist Gd3+ enhanced mineral deposition compared to that observed in 1.2 mM Ca2+. Over-expression of dominant negative (R185Q) CaR enhanced, whereas the calcimimetic R-568 attenuated, VSMC mineral deposition.
Conclusions: These results demonstrate that: a) VSMCs express a functional CaR; b) a reduction in CaR expression is associated with increased mineralization in vivo and in vitro; c) calcimimetics decrease mineral deposition by VSMC. These data suggest that calcimimetics may inhibit the development of vascular calcification in chronic kidney disease patients.
Time for primary review: 33 Days
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Cardiovasc Res 2009 81: 237-239.
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