Effect of Calcium and the Calcimimetic AMG 641 on Matrix-Gla Protein in Vascular Smooth Muscle Cells |
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Authors: | Francisco J Mendoza Julio Martinez-Moreno Yolanda Almaden Maria E Rodriguez-Ortiz Ignacio Lopez Jose Carlos Estepa Charles Henley Mariano Rodriguez Escolastico Aguilera-Tejero |
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Institution: | (1) Departamento de Medicina y Cirugia Animal, Universidad de Cordoba, Campus Universitario Rabanales, Ctra. Madrid-Cadiz km 396, 14014, Cordoba, Spain;(2) Unidad de Investigacion, Servicio de Nefrologia, Hospital Universitario Reina Sofia, Avda Menedez Pidal s/n, 14004 Cordoba, Spain;(3) Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA |
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Abstract: | Vascular calcification (VC) is frequently observed in patients with chronic renal failure and appears to be an active process
involving transdifferentiation of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Reports of VC prevention
in uremic rodents by calcimimetics coupled with identification of the calcium-sensing receptor (CaSR) in VSMCs led us to hypothesize
that CaSR activation in arterial cells and VSMCs may elicit expression of an endogenous inhibitor of VC. Toward this end,
we determined the effects of calcium and the calcimimetic AMG 641 on arterial wall and isolated VSMC expression of matrix-Gla
protein (MGP). Bovine VSMCs were incubated with increasing calcium chloride or AMG 641 concentrations, while in vivo experiments
were carried out on healthy and uremic rats. Both AMG 641 and hypercalcemia induced MGP expression in the arterial wall in
healthy and uremic rats. The results obtained in vitro supported those from in vivo experiments. In conclusion, selective
CaSR activation, either by extracellular calcium or AMG 641, increased MGP expression in vivo in the arterial wall and in
vitro in bovine VSMCs. This local upregulation of MGP expression provides one potential mechanism by which calcimimetics prevent
VC. |
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