Tissue Non-Specific Alkaline Phosphatase and Vascular Calcification: A Potential Therapeutic Target

Overview

Journal Curr Cardiol Rev

Publisher Bentham Science Publishers

Specialty Cardiology & Vascular Diseases

Date 2018 Nov 2

PMID 30381085

Citations 19

Authors

Daniel Azpiazu

Sergio Gonzalo

Ricardo Villa-Bellosta

Affiliations

Soon will be listed here.

Abstract

Vascular calcification is a pathologic phenomenon consisting of calcium phosphate crystal deposition in the vascular walls. Vascular calcification has been found to be a risk factor for cardiovascular diseases, due to its correlation with cardiovascular events and mortality, and it has been associated with aging, diabetes, and chronic kidney disease. Studies of vascular calcification have focused on phosphate homeostasis, primarily on the important role of hyperphosphatemia. Moreover, vascular calcification has been associated with loss of plasma pyrophosphate, one of the main inhibitors of calcification, thus indicating the importance of the phosphate/pyrophosphate ratio. Extracellular pyrophosphate can be synthesized from extracellular ATP by ecto-nucleotide pyrophosphatase/ phosphodiesterase, whereas pyrophosphate is hydrolyzed to phosphate by tissuenonspecific alkaline phosphatase, contributing to the formation of hydroxyapatite crystals. Over the last decade, vascular calcification has been the subject of numerous reviews and studies, which have revealed new agents and activities that may aid in explaining the complex physiology of this condition. This review summarizes current knowledge about alkaline phosphatase and its role in the process of vascular calcification as a key regulator of the phosphate/pyrophosphate ratio.

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References

Holtz K, Kantrowitz E . The mechanism of the alkaline phosphatase reaction: insights from NMR, crystallography and site-specific mutagenesis. FEBS Lett. 1999; 462(1-2):7-11. DOI: 10.1016/s0014-5793(99)01448-9. View

Farzaneh-Far A, Proudfoot D, Shanahan C, Weissberg P . Vascular and valvar calcification: recent advances. Heart. 2000; 85(1):13-7. PMC: 1729597. DOI: 10.1136/heart.85.1.13. View

Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P . PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am J Pathol. 2001; 158(2):543-54. PMC: 1850320. DOI: 10.1016/S0002-9440(10)63996-X. View

Proudfoot D, Shanahan C . Biology of calcification in vascular cells: intima versus media. Herz. 2001; 26(4):245-51. DOI: 10.1007/pl00002027. View

Lomashvili K, Cobbs S, Hennigar R, Hardcastle K, ONeill W . Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin. J Am Soc Nephrol. 2004; 15(6):1392-401. DOI: 10.1097/01.asn.0000128955.83129.9c. View

Lomashvili K, Khawandi W, ONeill W . Reduced plasma pyrophosphate levels in hemodialysis patients. J Am Soc Nephrol. 2005; 16(8):2495-500. DOI: 10.1681/ASN.2004080694. View

Robison R . The Possible Significance of Hexosephosphoric Esters in Ossification. Biochem J. 1923; 17(2):286-93. PMC: 1259346. DOI: 10.1042/bj0170286. View

Iyemere V, Proudfoot D, Weissberg P, Shanahan C . Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification. J Intern Med. 2006; 260(3):192-210. DOI: 10.1111/j.1365-2796.2006.01692.x. View

Narisawa S, Harmey D, Yadav M, ONeill W, Hoylaerts M, Millan J . Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification. J Bone Miner Res. 2007; 22(11):1700-10. DOI: 10.1359/jbmr.070714. View

10.

Lomashvili K, Garg P, Narisawa S, Millan J, ONeill W . Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification. Kidney Int. 2008; 73(9):1024-30. PMC: 3010853. DOI: 10.1038/ki.2008.26. View

11.

Millan J . Alkaline Phosphatases : Structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic Signal. 2008; 2(2):335-41. PMC: 2254479. DOI: 10.1007/s11302-005-5435-6. View

12.

Yamasaki K, Hagiwara H . Excess iron inhibits osteoblast metabolism. Toxicol Lett. 2009; 191(2-3):211-5. DOI: 10.1016/j.toxlet.2009.08.023. View

13.

BLUMENTHAL H, LANSING A, Wheeler P . Calcification of the Media of the Human Aorta and Its Relation to Intimal Arteriosclerosis, Ageing and Disease. Am J Pathol. 2009; 20(4):665-87. PMC: 2033157. View

14.

Yadav M, Simao A, Narisawa S, Huesa C, McKee M, Farquharson C . Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. J Bone Miner Res. 2010; 26(2):286-97. PMC: 3179344. DOI: 10.1002/jbmr.195. View

15.

ONeill W, Lomashvili K, Malluche H, Faugere M, Riser B . Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int. 2010; 79(5):512-7. PMC: 3183997. DOI: 10.1038/ki.2010.461. View

16.

Riser B, Barreto F, Rezg R, Valaitis P, Cook C, White J . Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia. Nephrol Dial Transplant. 2011; 26(10):3349-57. DOI: 10.1093/ndt/gfr039. View

17.

Villa-Bellosta R, Wang X, Millan J, Dubyak G, ONeill W . Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle. Am J Physiol Heart Circ Physiol. 2011; 301(1):H61-8. PMC: 3129914. DOI: 10.1152/ajpheart.01020.2010. View

18.

Shanahan C, Crouthamel M, Kapustin A, Giachelli C . Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011; 109(6):697-711. PMC: 3249146. DOI: 10.1161/CIRCRESAHA.110.234914. View

19.

Whyte M, Greenberg C, Salman N, Bober M, McAlister W, Wenkert D . Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012; 366(10):904-13. DOI: 10.1056/NEJMoa1106173. View

20.

Manes T, Glade K, Ziomek C, Millan J . Genomic structure and comparison of mouse tissue-specific alkaline phosphatase genes. Genomics. 1990; 8(3):541-54. DOI: 10.1016/0888-7543(90)90042-s. View