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

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.

• Authors: Ognen Ivanovski, Igor G Nikolov, Nobuhiko Joki, Axelle Caudrillier, Olivier Phan, Romuald Mentaverri, Julien Maizel, Yasuhiro Hamada, Thao Nguyen-Khoa, Masafumi Fukagawa, Said Kamel, Bernard Lacour, Tilman B Drüeke, Ziad A Massy
• Journal: Atherosclerosis (Atherosclerosis) Vol. 205 Issue 1 Pg. 55-62 (Jul 2009) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 19118829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Apolipoproteins E
• Fgf23 protein, mouse
• N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
• Phenethylamines
• Propylamines
• Receptors, Calcium-Sensing
• Phosphorus
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• Calcium

Topics

• Aniline Compounds (pharmacology)
• Animals
• Aorta (metabolism, pathology)
• Apolipoproteins E (genetics)
• Atherosclerosis (drug therapy)
• Calcinosis (drug therapy)
• Calcium (metabolism)
• Female
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (metabolism)
• Kidney Failure, Chronic (metabolism)
• Mice
• Mice, Transgenic
• Phenethylamines
• Phosphorus (metabolism)
• Propylamines
• Receptors, Calcium-Sensing (metabolism)
• Uremia (drug therapy)