Effect of calcium and the calcimimetic AMG 641 on matrix-Gla protein in vascular smooth muscle cells.

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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