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Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2011 Jul; Vol. 301 (1), pp. H61-8. Date of Electronic Publication: 2011 Apr 13. - Publication Year :
- 2011
-
Abstract
- Extracellular inorganic pyrophosphate (ePP(i)) is an important endogenous inhibitor of vascular calcification, but it is not known whether systemic or local vascular PP(i) metabolism controls calcification. To determine the role of ePP(i) in vascular smooth muscle, we identified the pathways responsible for ePP(i) production and hydrolysis in rat and mouse aortas and manipulated them to demonstrate their role in the calcification of isolated aortas in culture. Rat and mouse aortas contained mRNA for ectonucleotide pyrophosphatase/phosphodiesterases (NPP1-3), the putative PP(i) transporter ANK, and tissue-nonspecific alkaline phosphatase (TNAP). Synthesis of PP(i) from ATP in aortas was blocked by β,γ-methylene-ATP, an inhibitor of NPPs. Aortas from mice lacking NPP1 (Enpp1(-/-)) did not synthesize PP(i) from ATP and exhibited increased calcification in culture. Although ANK-mediated transport of PP(i) could not be demonstrated in aortas, aortas from mutant (ank/ank) mice calcified more in culture than did aortas from normal (ANK/ANK) mice. Hydrolysis of PP(i) was reduced 25% by β,γ-methylene-ATP and 50% by inhibition of TNAP. Hydrolysis of PP(i) was increased in cells overexpressing TNAP or NPP3 but not NPP1 and was not reduced in Enpp1(-/-) aortas. Overexpression of TNAP increased calcification of cultured aortas. The results show that smooth muscle NPP1 and TNAP control vascular calcification through effects on synthesis and hydrolysis of ePP(i), indicating an important inhibitory role of locally produced PP(i). Smooth muscle ANK also affects calcification, but this may not be mediated through transport of PP(i). NPP3 is identified as an additional pyrophosphatase that could influence vascular calcification.
- Subjects :
- Adenosine Triphosphate metabolism
Adenoviridae genetics
Alkaline Phosphatase antagonists & inhibitors
Alkaline Phosphatase biosynthesis
Alkaline Phosphatase genetics
Animals
Arteries metabolism
DNA Primers
Extracellular Space drug effects
Extracellular Space enzymology
Humans
Mice
Mice, Knockout
Muscle, Smooth, Vascular enzymology
Organ Culture Techniques
Phosphoric Diester Hydrolases
Pyrophosphatases antagonists & inhibitors
RNA, Messenger biosynthesis
RNA, Messenger genetics
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Vascular Calcification genetics
Calcification, Physiologic physiology
Diphosphates metabolism
Extracellular Space metabolism
Muscle, Smooth, Vascular metabolism
Vascular Calcification metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 301
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 21490328
- Full Text :
- https://doi.org/10.1152/ajpheart.01020.2010