期刊
ATHEROSCLEROSIS
卷 205, 期 1, 页码 55-62出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2008.10.043
关键词
Calcimimetics; Uremia; Calcification; Calcium-sensing receptor; FGF23; Atherosclerosis; ApoE(-/-) mouse
资金
- Amgen, Thousand Oaks, CA, USA
- NATO Science and Security Program
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 I 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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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