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Updated: Jan 4, 2026
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson-Gilford
1Fundación Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain metabol@hotmail.com.
Insights
Pyrophosphate deficiency contributes to vascular calcification in Hutchinson-Gilford progeria syndrome (HGPS). Combined ATP, levamisole, and ARL67156 treatment improved pyrophosphate levels, prevented calcification, and extended longevity in HGPS mice.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Biology
Background:
- Hutchinson-Gilford progeria syndrome (HGPS) is characterized by premature aging and severe vascular calcification.
- Pyrophosphate (PPi) deficiency is implicated in the excessive vascular calcification observed in HGPS.
- Adenosine triphosphate (ATP) metabolism plays a critical role in regulating PPi levels.
Purpose of the Study:
- To investigate the role of pyrophosphate metabolism in HGPS-associated vascular calcification.
- To evaluate the therapeutic potential of modulating pyrophosphate levels in HGPS.
Main Methods:
- Assessed pyrophosphate synthesis and hydrolysis in wild-type and HGPS mouse models.
- Utilized enzyme inhibitors (levamisole for TNAP, ARL67156 for eNTPD) to modulate pyrophosphate metabolism.
- Administered ATP, alone and in combination with inhibitors, to HGPS mice to assess effects on vascular calcification and longevity.
Main Results:
- HGPS aortas and blood showed reduced pyrophosphate synthesis and increased hydrolysis compared to wild-type.
- Combined treatment with ATP, levamisole, and ARL67156 normalized pyrophosphate levels ex vivo.
- ATP treatment alone prevented vascular calcification but not mortality in HGPS mice.
- Combined ATP, levamisole, and ARL67156 treatment prevented vascular calcification and extended longevity by 12% in HGPS mice.
Conclusions:
- Pyrophosphate deficiency is a key factor in HGPS vascular calcification.
- Combined inhibition of pyrophosphate hydrolysis and supplementation with ATP offers a promising therapeutic strategy for HGPS.
- This approach may represent a novel treatment for children with HGPS, addressing both vascular complications and potentially improving lifespan.
Abstract:
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.
