ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson-Gilford progeria syndrome

Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23698-23704. doi: 10.1073/pnas.1910972116. Epub 2019 Nov 5.

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.

Keywords: ATP; Hutchinson–Gilford progeria syndrome; aging; pyrophosphate; vascular calcification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives*
  • Adenosine Triphosphate / metabolism*
  • Adenosine Triphosphate / therapeutic use
  • Alkaline Phosphatase / antagonists & inhibitors
  • Alkaline Phosphatase / physiology*
  • Animals
  • Antigens, CD / physiology
  • Aortic Diseases / enzymology
  • Aortic Diseases / prevention & control*
  • Apyrase / antagonists & inhibitors*
  • Apyrase / deficiency
  • Apyrase / physiology
  • Calcinosis / enzymology
  • Calcinosis / prevention & control*
  • Diphosphates / metabolism*
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Humans
  • Lamin Type A / genetics
  • Levamisole / therapeutic use*
  • Longevity / drug effects
  • Male
  • Mice
  • Mice, Transgenic
  • Myocytes, Smooth Muscle / metabolism
  • Phosphoric Diester Hydrolases / deficiency
  • Phosphoric Diester Hydrolases / physiology
  • Progeria / drug therapy*
  • Progeria / genetics
  • Progeria / metabolism
  • Progeria / pathology
  • Pyrophosphatases / antagonists & inhibitors*
  • Pyrophosphatases / deficiency
  • Pyrophosphatases / physiology
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Real-Time Polymerase Chain Reaction

Substances

  • 6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP
  • Antigens, CD
  • Diphosphates
  • LMNA protein, human
  • Lamin Type A
  • RNA, Small Interfering
  • Levamisole
  • diphosphoric acid
  • Adenosine Triphosphate
  • ALPL protein, mouse
  • Alkaline Phosphatase
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases
  • Apyrase
  • CD39 antigen

Associated data

  • figshare/10.6084/m9.figshare.9978794