The calcimimetic R-568 retards uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE-/-) mice

Atherosclerosis. 2009 Jul;205(1):55-62. doi: 10.1016/j.atherosclerosis.2008.10.043. Epub 2008 Nov 18.

Abstract

Objective: Secondary hyperparathyroidism of chronic kidney disease promotes vascular calcification. Calcimimetics reduce serum parathyroid hormone, calcium (Ca), and phosphorus by calcium-sensing receptor (CaR) activation. Here we examined possible effects of the calcimimetic R-568 (R-568) on the progression of aortic calcification and atherosclerosis in apoE(-/-) mice with chronic renal failure (CRF) and the potential implication of aortic smooth muscle cell CaR.

Methods and results: ApoE(-/-) mice were assigned to 3 CRF groups and 1 non-CRF group receiving daily gavage with R-568, calcitriol, or vehicle. Serum Ca and phosphorus and parathyroid gland volume of CRF mice were decreased by R-568, whereas elevated serum FGF23 and total cholesterol remained unchanged. Both aortic plaque and non-plaque calcification was lower in R-568 mice, and so was atherosclerotic plaque area fraction. In vitro, R-568 induced a decrease in smooth muscle cell calcification when cultured in high phosphate medium. This decrease was abolished in CaR-SiRNA-transfected cells.

Conclusions: The calcimimetic R-568 delayed the progression of both aortic calcification and atherosclerosis in uremic apoE(-/-) mice. This effect was mediated via a better control of hyperparathyroidism including serum Ca and phosphorus. Direct vascular CaR activation also could have played a role in the observed effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / genetics*
  • Atherosclerosis / drug therapy*
  • Calcinosis / drug therapy*
  • Calcium / metabolism
  • Female
  • Fibroblast Growth Factors / metabolism
  • Kidney Failure, Chronic / metabolism
  • Mice
  • Mice, Transgenic*
  • Phenethylamines
  • Phosphorus / metabolism
  • Propylamines
  • Receptors, Calcium-Sensing / metabolism
  • Uremia / drug therapy*

Substances

  • Aniline Compounds
  • Apolipoproteins E
  • N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
  • Phenethylamines
  • Propylamines
  • Receptors, Calcium-Sensing
  • Phosphorus
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Calcium