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Calcimimetics increase CaSR expression and reduce mineralization in vascular smooth muscle cells: mechanisms of action.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2014 Feb 01; Vol. 101 (2), pp. 256-65. Date of Electronic Publication: 2013 Nov 11. - Publication Year :
- 2014
-
Abstract
- Aims: Vascular calcification (VC) contributes to morbidity and mortality in patients with chronic kidney disease (CKD). Allosteric modulators of the calcium (Ca)-sensing receptor (CaSR) may slow the progression of VC in CKD patients either by reducing serum parathyroid hormone (PTH), Ca, and phosphate levels or by a direct effect on the vessel wall. The aim of this study was to examine the effects of calcimimetics on CaSR expression, cell phenotype, and mineral deposition in human vascular smooth muscle cells (h-VSMCs).<br />Methods and Results: Primary h-VSMCs were exposed for 14 days to increasing concentrations of Ca(2+) (from 1.8 to 5 mmol/L) in the presence or absence of calcimimetics R-568 or AMG 641 (0.1 μmol/L). Mineralization was detected by Alizarin red staining, and the cell phenotype was assessed using immunocytochemistry and qRT-PCR. CaSR expression was evaluated using flow cytometry. Short- and long-term exposure (1 day to 14 days) of h-VSMCs to calcimimetics promoted CaSR protein transport from the endoplasmic reticulum to the plasma membrane with enhanced CaSR expression on the cell surface, together with an increase in total cell CaSR expression due to enhanced biosynthesis. In pro-mineralizing conditions, exposure to calcimimetics counteracted the Ca(2+)-dependent reduction of CaSR expression, decreased matrix collagen secretion, and mineral deposition by ~90%. These effects involved CaSR activation since it could be inhibited by CaSR siRNA, but not scrambled siRNA.<br />Conclusions: The calcimimetic-dependent increase in biosynthesis and activation of the CaSR in h-VSMCs probably play a key role in the protection against calcium-induced VC.
- Subjects :
- Cell Membrane drug effects
Cell Membrane metabolism
Cells, Cultured
Collagen Type I metabolism
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum metabolism
Humans
Muscle, Smooth, Vascular metabolism
Myocytes, Smooth Muscle metabolism
Phenotype
Propylamines
Protein Transport
RNA Interference
Receptors, Calcium-Sensing genetics
Receptors, Calcium-Sensing metabolism
Time Factors
Transfection
Up-Regulation
Vascular Calcification genetics
Vascular Calcification metabolism
Aniline Compounds pharmacology
Biphenyl Compounds pharmacology
Calcimimetic Agents pharmacology
Calcium metabolism
Muscle, Smooth, Vascular drug effects
Myocytes, Smooth Muscle drug effects
Phenethylamines pharmacology
Receptors, Calcium-Sensing drug effects
Vascular Calcification prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 101
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 24217682
- Full Text :
- https://doi.org/10.1093/cvr/cvt249