title: Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment.
abstract: BACKGROUND
  Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly of myocardial infarction or stroke. The goal of this study was to investigate mechanisms that cause excessive vascular calcification in HGPS.
  
  
  RESULTS
  We performed expression and functional studies in wild-type mice and knock-in Lmna(G609G/+) mice expressing progerin, which mimic the main clinical manifestations of HGPS. Lmna(G609G/+) mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells from these progeroid animals had an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing vascular smooth muscle cells is associated with increased expression and activity of tissue-nonspecific alkaline phosphatase and mitochondrial dysfunction, which leads to reduced ATP synthesis. Accordingly, Lmna(G609G/+) vascular smooth muscle cells are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of Lmna(G609G/+) mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice.
  
  
  CONCLUSIONS
  Excessive vascular calcification in Lmna(G609G) mice is caused by reduced extracellular accumulation of pyrophosphate that results from increased tissue-nonspecific alkaline phosphatase activity and diminished ATP availability caused by mitochondrial dysfunction in vascular smooth muscle cells. Excessive calcification is ameliorated on pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, because progerin progressively accumulates in the vascular tissue of individuals without HGPS.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Villa-Bellosta
authors.forename: José
authors.initials: J
authors.lastname: Rivera-Torres
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.forename: José A
authors.initials: JA
authors.lastname: Enriquez
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D011756:Diphosphates / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008931:Mitochondria, Muscle / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011371:Progeria / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome; D061205:Vascular Calcification / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D011756:Diphosphates; D034904:Lamin Type A; C576142:Lmna protein, mouse; C107241:diphosphoric acid; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase
keywords: ATP; Hutchinson-Gilford progeria syndrome; muscle, smooth; progerin; pyrophosphate; tissue-non specific alkaline phosphatase; vascular calcification