pyrophosphate and Aortic-Diseases

We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.. Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

Topics: Abnormalities, Multiple; Aortic Diseases; Basal Ganglia Diseases; Calcinosis; Cartilage Diseases; Dental Enamel Hypoplasia; Diphosphates; Enzyme Replacement Therapy; Gaucher Disease; Hand Deformities, Congenital; Humans; Hyperostosis, Cortical, Congenital; Hyperphosphatemia; Interferons; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Phosphates; Progeria; Pseudoxanthoma Elasticum; Pulmonary Valve Stenosis; Vascular Calcification

Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson-Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.

Topics: Adenosine Triphosphate; Alkaline Phosphatase; Animals; Antigens, CD; Aortic Diseases; Apyrase; Calcinosis; Diphosphates; Disease Models, Animal; Gene Knock-In Techniques; Humans; Lamin Type A; Levamisole; Longevity; Male; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Phosphoric Diester Hydrolases; Progeria; Pyrophosphatases; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering

Topics: Animals; Aorta; Aortic Diseases; Diphosphates; Vascular Calcification

Plasma levels of pyrophosphate, an endogenous inhibitor of vascular calcification, are reduced in end-stage renal disease and correlate inversely with arterial calcification. However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels. This was tested in an animal model in which aortas were transplanted between normal mice and Enpp1(-/-) mice lacking ectonucleotide pyrophosphatase phosphodiesterase, the enzyme that synthesizes extracellular pyrophosphate. Enpp1(-/-) mice had very low plasma pyrophosphate and developed aortic calcification by 2 months that was greatly accelerated with a high-phosphate diet. Aortas of Enpp1(-/-) mice showed no further calcification after transplantation into wild-type mice fed a high-phosphate diet. Aorta allografts of wild-type mice calcified in Enpp1(-/-) mice but less so than the adjacent recipient Enpp1(-/-) aorta. Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1(-/-) mice, demonstrating that transplantation per se did not affect calcification. Histology revealed medial calcification with no signs of rejection. Thus, normal levels of extracellular pyrophosphate are sufficient to prevent vascular calcification, and systemic Enpp1 deficiency is sufficient to produce vascular calcification despite normal vascular extracellular pyrophosphate production. This establishes an important role for circulating extracellular pyrophosphate in preventing vascular calcification.

Topics: Animals; Aorta; Aortic Diseases; Calcium; Diphosphates; Disease Models, Animal; Disease Progression; Mice, Inbred C57BL; Mice, Knockout; Phosphoric Diester Hydrolases; Phosphorus, Dietary; Pyrophosphatases; Time Factors; Vascular Calcification

Topics: Adolescent; Adult; Aged; Aorta, Abdominal; Aortic Diseases; Diphosphates; Heart; Heart Ventricles; Hemodynamics; Humans; Middle Aged; Prognosis; Technetium; Technetium Tc 99m Pyrophosphate; Tomography, Emission-Computed

Two diphosphonates containing the P-C-P bond, CH(3)C(OH)(PO(3)HNa)(2) and H(2)C(PO(3)HNa)(2), inhibit the crystallization of calcium phosphate in vitro and prevent aortic calcification of rats given large amounts of vitamin D(3). The diphosphonates therefore have effects similar to those described for compounds containing the P-O-P bond but are active when administered orally.

Topics: Animals; Aortic Diseases; Calcinosis; Cholecalciferol; Crystallization; Diphosphates; Hydrogen-Ion Concentration; Organophosphonates; Phosphates; Rats; X-Ray Diffraction

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Cholecalciferol; Diphosphates; Female; Hypercalcemia; Kidney; Phosphates; Rats

Topics: Animals; Aortic Diseases; Bone Resorption; Calcinosis; Calcium Phosphates; Chemical Phenomena; Chemical Precipitation; Chemistry; Cholecalciferol; Diphosphates; Hypercalcemia; Mice; Organophosphonates; Pyrophosphatases; Rats

Topics: Animals; Aortic Diseases; Calcinosis; Diphosphates; Phosphates; Rats; Vitamin D