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


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.
Ivanovski
Ognen
O
Inserm Unit 845, Necker Hospital, Paris-Descartes University Paris V, Paris, France.
Nikolov
Igor G
IG
Joki
Nobuhiko
N
Caudrillier
Axelle
A
Phan
Olivier
O
Mentaverri
Romuald
R
Maizel
Julien
J
Hamada
Yasuhiro
Y
Nguyen-Khoa
Thao
T
Fukagawa
Masafumi
M
Kamel
Said
S
Lacour
Bernard
B
Drüeke
Tilman B
TB
Massy
Ziad A
ZA
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy*; D002114:Calcinosis / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010627:Phenethylamines; D010758:Phosphorus / Q000378:metabolism; D011437:Propylamines; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D014511:Uremia / Q000188:drug therapy*
D000814:Aniline Compounds; D001057:Apolipoproteins E; C000717428:Fgf23 protein, mouse; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002118:Calcium