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Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells

Alam, Masih-Ul, Kirton, John Paul, Wilkinson, Fiona L., Towers, Emily, Sinha, Smeeta, Rouhi, Mansour, Vizard, Thomas Neill, Sage, Andrew P., Martin, David, Ward, Donald T., Alexander, Marie Yvonne, Riccardi, Daniela and Canfield, Ann E. 2009. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovascular Research 81 (2) , pp. 260-268. 10.1093/cvr/cvn279

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QP Physiology
R Medicine > RB Pathology
Publisher: Oxford Journals
ISSN: 0008-6363
Last Modified: 04 Jun 2017 02:05

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