title: Growth-associated hyperphosphatemia in young recipients accelerates aortic allograft calcification in a rat model.
abstract: OBJECTIVE
  Cardiovascular allografts in the young have limited durability because of early graft calcification. The objective of this study was to examine the hypothesis that growth-associated hyperphosphatemia in youth accelerates aortic allograft calcification by osteogenic transformation of graft medial smooth muscle cells (SMCs).
  
  
  METHODS
  The descending aortas of donor rats were subcutaneously transplanted into recipients. Syngeneic (Lewis-to-Lewis) transplantations between 3-week-old "young" (Y) rats and between 10-week-old "adult" (A) rats were combined with standard (ST, 0.9% phosphate) and low-phosphate (LP, 0.2%) diets, resulting in Y-ST, Y-LP, and A-ST groups. Allotransplantations (Brown-Norway-to-Lewis) involving these ages and diets were also made. The grafts and sera were retrieved from recipients after 14 days. Cultured rat aortic SMCs were used to analyze the effects of tumor necrosis factor-alpha (TNF-α) and phosphate on SMC calcification.
  
  
  RESULTS
  In vivo, serum phosphate levels were higher in Y-ST (11.5 mg/dL) than those in Y-LP (8.9 mg/dL) and A-ST (8.5 mg/dL). Graft medial calcification appeared severe only in Y-ST. Allotransplants did not affect these outcomes. Graft medial cells showed phenotypic changes (contractile to synthetic) and osteogenic transformation (α-smooth muscle actin to Runx2 and osteocalcin), together with up-regulated proinflammatory TNF-α and sodium-phosphate cotransporter, Pit-1, despite ages and diets. In vitro, TNF-α induced phenotypic changes and osteogenic transformation of SMCs with Pit-1 up-regulation, but SMC calcification occurred only with high phosphate (4.5 mmol/L).
  
  
  CONCLUSIONS
  Growth-associated hyperphosphatemia with inflammatory responses may be essential for accelerating allograft calcification in youth and could be a therapeutic target.
authors.affiliation: Department of Cardiothoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan. hyamauchi-tky@umin.ac.jp
authors.forename: Haruo
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Noboru
authors.initials: N
authors.lastname: Motomura
authors.forename: Ung-Il
authors.initials: UI
authors.lastname: Chung
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Daiya
authors.initials: D
authors.lastname: Takai
authors.forename: Aya
authors.initials: A
authors.lastname: Saito
authors.forename: Minoru
authors.initials: M
authors.lastname: Ono
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takamoto
mesh_terms: D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D054559:Hyperphosphatemia / Q000097:blood / Q000150:complications*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000637:transplantation / Q000648:ultrastructure; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D010710:Phosphates / Q000097:blood; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D061205:Vascular Calcification / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology
chemical_list: D000199:Actins; D015415:Biomarkers; D050659:Core Binding Factor Alpha 1 Subunit; D018836:Inflammation Mediators; D015675:Osteocalcin; D010710:Phosphates; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D014409:Tumor Necrosis Factor-alpha; C493717:Runx2 protein, rat; C493588:Slc20a1 protein, rat; C498862:Acta2 protein, rat