on February 12, 2009
Published online before print February 12, 2009, doi: 10.1161/ATVBAHA.108.183384
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Submitted on October 1, 2008
Accepted on February 4, 2009
Phosphonoformic Acid Prevents Vascular Smooth Muscle Cell Calcification by Inhibiting Calcium-Phosphate Deposition
Ricardo Villa-Bellosta and Víctor Sorribas *
From the Laboratory of Molecular Toxicology, University of Zaragoza, Spain.
* To whom correspondence should be addressed. E-mail: sorribas{at}unizar.es.
Objective—The role of inorganic phosphate in the pathogenesis of vascular calcification (VC) has been studied extensively in recent years. Phosphonoformic acid (PFA), an inhibitor of type II Pi transporters, has been traditionally used to study the involvement of Pi transport in VC, because PFA also prevents calcium deposition in vitro. However, aortic vascular smooth muscle cells (VSMCs) only express PFA-resistant, type III transporters (Pit-1 and Pit-2). Therefore, in this article we have studied the mechanism of VC prevention by PFA.
Methods and Results—Radiotracer Pi uptake in rat VSMCs was not inhibited at the concentrations at which PFA prevents calcification. Alternative mechanisms whereby PFA could prevent calcification, such as cytotoxicity or phosphodiesterase inhibition, have also been excluded. The progression of calcification also took place in fixed cells. The kinetics of VC prevention by PFA, pyrophosphate, phosphonoacetate, and bisphosphonates was similar in live and fixed cells, showing mean effective concentrations in the micromolar range.
Conclusions—PFA mainly prevents VC through a physicochemical mechanism that is independent of any cellular metabolic activity, including Pi transport. Conversely, PFA seems to act similarly to its chemical analogues, inorganic pyrophosphate, and bisphosphonates, as suggested decades ago.
Key words: phosphonoformic acid • foscarnet • vascular calcification • phosphate transport • Pit-1
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  R. Villa-Bellosta and V. Sorribas Different effects of arsenate and phosphonoformate on Pi transport adaptation in opossum kidney cells Am J Physiol Cell Physiol, January 1, 2009; 297(3): C516 - C525. [Abstract] [Full Text] [PDF]
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