This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 98/7/905    most recent 01.RES.0000216409.20863.e7v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Giachelli, C. M. Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Giachelli, C. M. Related Collections Ion channels/membrane transport Other Vascular biology Related Article

(Circulation Research. 2006;98:905.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Role of the Sodium-Dependent Phosphate Cotransporter, Pit-1, in Vascular Smooth Muscle Cell Calcification

Xianwu Li, Hsueh-Ying Yang, Cecilia M. Giachelli

From the Department of Bioengineering, University of Washington, Seattle.

Correspondence to Cecilia M. Giachelli, Bioengineering, Box 351720, University of Washington, Bagley Hall, Rm 479, Okanagon Ln, Seattle, WA 98195-1720. E-mail ceci{at}u.washington.edu

Vascular calcification is associated with cardiovascular morbidity and mortality. Hyperphosphatemia is an important contributor to vascular calcification. Our previous studies demonstrated that elevated phosphate induces calcification of smooth muscle cells (SMC) in vitro. Inhibition of phosphate transport by phosphonoformic acid blocked phosphate-induced calcification, implicating sodium-dependent phosphate cotransporters in this process. In the present study, we have investigated the role of the type III sodium-dependent phosphate cotransporter, Pit-1, in SMC calcification in vitro. Human SMC stably expressing Pit-1 small interfering double-stranded RNA (SMC-iRNA) were established using a retroviral system. SMC-iRNA had decreased Pit-1 mRNA and protein levels and sodium-dependent phosphate transport activity compared with the control transduced cells (SMC-CT) (2.9 versus 9.78 nmol/mg protein per 30 minutes, respectively). Furthermore, phosphate-induced SMC calcification was significantly inhibited in SMC-iRNA compared with SMC-CT at all time points examined. Overexpression of Pit-1 restored phosphate uptake and phosphate-induced calcification in Pit-1 deficient cells. Mechanistically, although Pit-1–mediated SMC calcification was not associated with apoptosis or cell-derived vesicles, inhibition of phosphate uptake in Pit-1 knockdown cells blocked the induction of the osteogenic markers Cbfa-1 and osteopontin. Our results indicate that phosphate uptake through Pit-1 is essential for SMC calcification and phenotypic modulation in response to elevated phosphate.

Key Words: sodium-dependent phosphate cotransporter • Pit-1 • vascular calcification • smooth muscle cell

Related Article:

Pitting Phosphate Transport Inhibitors Against Vascular Calcification

Linda L. Demer and Yin Tintut
Circ. Res. 2006 98: 857-859. [Full Text] [PDF]

This article has been cited by other articles:

				L. L. Demer and Y. Tintut Vascular Calcification: Pathobiology of a Multifaceted Disease Circulation, June 3, 2008; 117(22): 2938 - 2948. [Full Text] [PDF]

				S. Mathew, K. S. Tustison, T. Sugatani, L. R. Chaudhary, L. Rifas, and K. A. Hruska The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1092 - 1105. [Abstract] [Full Text] [PDF]

				K. A. Johnson, M. Polewski, and R. A. Terkeltaub Transglutaminase 2 Is Central to Induction of the Arterial Calcification Program by Smooth Muscle Cells Circ. Res., March 14, 2008; 102(5): 529 - 537. [Abstract] [Full Text] [PDF]

				M. Liberman, E. Bassi, M. K. Martinatti, F. C. Lario, J. Wosniak Jr, P. M.A. Pomerantzeff, and F. R.M. Laurindo Oxidant Generation Predominates Around Calcifying Foci and Enhances Progression of Aortic Valve Calcification Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 463 - 470. [Abstract] [Full Text] [PDF]

				L. V. Virkki, J. Biber, H. Murer, and I. C. Forster Phosphate transporters: a tale of two solute carrier families Am J Physiol Renal Physiol, September 1, 2007; 293(3): F643 - F654. [Abstract] [Full Text] [PDF]

				S. Ravera, L. V. Virkki, H. Murer, and I. C. Forster Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements Am J Physiol Cell Physiol, August 1, 2007; 293(2): C606 - C620. [Abstract] [Full Text] [PDF]

				Y. Yoshiko, G. A. Candeliere, N. Maeda, and J. E. Aubin Osteoblast Autonomous Pi Regulation via Pit1 Plays a Role in Bone Mineralization Mol. Cell. Biol., June 15, 2007; 27(12): 4465 - 4474. [Abstract] [Full Text] [PDF]

				W. N. Addison, F. Azari, E. S. Sorensen, M. T. Kaartinen, and M. D. McKee Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity J. Biol. Chem., May 25, 2007; 282(21): 15872 - 15883. [Abstract] [Full Text] [PDF]

				R. Villa-Bellosta, Y. E. Bogaert, M. Levi, and V. Sorribas Characterization of Phosphate Transport in Rat Vascular Smooth Muscle Cells: Implications for Vascular Calcification Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1030 - 1036. [Abstract] [Full Text] [PDF]

				M. Julien, D. Magne, M. Masson, M. Rolli-Derkinderen, O. Chassande, C. Cario-Toumaniantz, Y. Cherel, P. Weiss, and J. Guicheux Phosphate Stimulates Matrix Gla Protein Expression in Chondrocytes through the Extracellular Signal Regulated Kinase Signaling Pathway Endocrinology, February 1, 2007; 148(2): 530 - 537. [Abstract] [Full Text] [PDF]

				S. Mathew, R. J. Lund, F. Strebeck, K. S. Tustison, T. Geurs, and K. A. Hruska Reversal of the Adynamic Bone Disorder and Decreased Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy J. Am. Soc. Nephrol., January 1, 2007; 18(1): 122 - 130. [Abstract] [Full Text] [PDF]

				R. C. Johnson, J. A. Leopold, and J. Loscalzo Vascular Calcification: Pathobiological Mechanisms and Clinical Implications Circ. Res., November 10, 2006; 99(10): 1044 - 1059. [Abstract] [Full Text] [PDF]

				K. D. O'Brien Pathogenesis of Calcific Aortic Valve Disease: A Disease Process Comes of Age (and a Good Deal More) Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1721 - 1728. [Abstract] [Full Text] [PDF]

				P. J. Pagano and M. J. Haurani Vascular Cell Locomotion: Osteopontin, NADPH Oxidase, and Matrix Metalloproteinase-9 Circ. Res., June 23, 2006; 98(12): 1453 - 1455. [Full Text] [PDF]

				L. L. Demer and Y. Tintut Pitting Phosphate Transport Inhibitors Against Vascular Calcification Circ. Res., April 14, 2006; 98(7): 857 - 859. [Full Text] [PDF]