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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:761.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Phosphonoformic Acid Prevents Vascular Smooth Muscle Cell Calcification by Inhibiting Calcium-Phosphate Deposition

Ricardo Villa-Bellosta; Víctor Sorribas

From the Laboratory of Molecular Toxicology, University of Zaragoza, Spain.

Correspondence to Víctor Sorribas, Laboratory of Molecular Toxicology, University of Zaragoza, Veterinary Faculty, Calle Miguel Servet 177, 50013 Zaragoza, Spain. 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.

Phosphonoformate prevents calcification in vascular smooth muscle cells but does not inhibit Pi transport. Cytotoxicity and phosphodiesterase inhibition by phosphonoformate have also been discarded. Phosphonoformate prevents calcification in fixed cells, which suggests that the mechanism is independent of any cellular activity. We conclude that phosphonoformate acts as a pyrophosphate analogue.

Key Words: phosphonoformic acid • bisphosphonate • vascular calcification • phosphate transport • Pit-1

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