Phosphate Regulation of Vascular Smooth Muscle Cell Calcification

Circulation Research - Tập 87 Số 7 - 2000
Shuichi Jono1, Marc D. McKee1, Charles E. Murry1, Atsushi Shioi1, Yoshiki Nishizawà1, Katsuhito Mori1, Hirotoshi Morii1, Cecilia M. Giachelli1
1From the Departments of Bioengineering (S.J., C.M.G.) and Pathology (C.E.M., C.M.G.), University of Washington, Seattle, Wash; Dentistry (M.D.M) and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada; and Second Department of Internal Medicine (A.S., Y.N., K.M., H.M.), Osaka City University Medical School, Osaka, Japan.

Tóm tắt

Abstract —Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.

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Circulation Research

Tập 87 Số 7

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