Role of the extracellular ATP/pyrophosphate metabolism cycle in vascular calcification

Abstract

Conventionally, ATP is considered to be the principal energy source in cells. However, over the last few years, a novel role for ATP as a potent extracellular signaling molecule and the principal source of extracellular pyrophosphate, the main endogenous inhibitor of vascular calcification, has emerged. A large body of evidence suggests that two principal mechanisms are involved in the initiation and progression of ectopic calcification: high phosphate concentration and pyrophosphate deficiency. Pathologic calcification of cardiovascular structures, or vascular calcification, is a feature of several genetic diseases and a common complication of chronic kidney disease, diabetes, and aging. Previous studies have shown that the loss of function of several enzymes and transporters involved in extracellular ATP/pyrophosphate metabolism is associated with vascular calcification. Therefore, pyrophosphate homeostasis should be further studied to facilitate the design of novel therapeutic approaches for ectopic calcification of cardiovascular structures, including strategies to increase pyrophosphate concentrations by targeting the ATP/pyrophosphate metabolism cycle.

Keywords: ATP; Calcium; Phosphate; Pyrophosphate; Vascular calcification.

Fig. 1

Schematic representation of calcification. Inorganic phosphate (Pi) exists in several forms including trihydrogen phosphate (H₃P0₄), dihydrogen phosphate ion (H₂PO₄⁻), hydrogen phosphate ion (HPO₄²⁻), and phosphate ion (PO₄²⁻). Phosphate charge is neutralized with calcium forming several calcium-phosphate salts including, anhydrous monocalcium phosphate (Ca(H₂PO₄)₂), anhydrous dicalcium phosphate (CaHPO₄), β-tricalcium phosphate (β-Ca₃(PO₄)₂), monocalcium phosphate monohydrate (Ca(H₂PO₄)₂H₂O), and dicalcium phosphate dihydrate (CaHPO₄2H₂0; also called Brushite). The final product of the calcium and phosphate reaction is crystalline hydroxyapatite (Ca₁₀(PO₄)₆(OH)), the main component of bone and calcified tissues and two of its precursors, amorphous calcium phosphate (Ca₉(PO₄)₆nH₂O), and octocalcium phosphate (Ca₈H₂(PO₄)₆5H₂O). Pyrophosphate directly inhibits the formation and growth of these phosphate-calcium crystals. Ks, solubility product constant

Fig. 2

Schematic representation of the ectoenzymes and transporters involved in the extracellular ATP/pyrophosphate metabolism cycle. eNPP, ectonucleotide pyrophosphatase phosphodiesterase; eNTPD, ectonucleoside triphosphate diphosphohydrolase; ATP, adenosine-5’-triphosphate; ADP, adenosine-5’-diphosphate; AMP, adenosine-5’-monophosphate; Ado, adenosine; TNAP, tissue nonspecific alkaline phosphatase; ANK, the progressive ankylosis protein; NaPi, sodium-phosphate cotransporters; NT5E, ecto-5′nucletotidase; eNT1, equilibrative nucleoside transporter 1. ATP channel includes ABCC6