title: Cellular Changes during Renal Failure-Induced Inflammatory Aortic Valve Disease.
abstract: BACKGROUND
  Aortic valve calcification (AVC) secondary to renal failure (RF) is an inflammation-regulated process, but its pathogenesis remains unknown. We sought to assess the cellular processes that are involved in the early phases of aortic valve disease using a unique animal model of RF-associated AVC.
  
  
  METHODS
  Aortic valves were obtained from rats that were fed a uremia-inducing diet exclusively for 2, 3, 4, 5, and 6 weeks as well as from controls. Pathological examination of the valves included histological characterization, von Kossa staining, and antigen expression analyses.
  
  
  RESULTS
  After 2 weeks, we noted a significant increase in urea and creatinine levels, reflecting RF. RF parameters exacerbated until the Week 5 and plateaued. Whereas no histological changes or calcification was observed in the valves of any study group, macrophage accumulation became apparent as early as 2 weeks after the diet was started and rose after 3 weeks. By western blot, osteoblast markers were expressed after 2 weeks on the diet and decreased after 6 weeks. Collagen 3 was up-regulated after 3 weeks, plateauing at 4 weeks, whereas collagen 1 levels peaked at 2 and 4 weeks. Fibronectin levels increased gradually until Week 5 and decreased at 6 weeks. We observed early activation of the ERK pathway, whereas other pathways remained unchanged.
  
  
  CONCLUSIONS
  We concluded that RF induces dramatic changes at the cellular level, including macrophage accumulation, activation of cell signaling pathway and extracellular matrix modification. These changes precede valve calcification and may increase propensity for calcification, and have to be investigated further.
authors.affiliation: Schulich Heart Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Mony
authors.initials: M
authors.lastname: Shuvy
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Suzan
authors.initials: S
authors.lastname: Abedat
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Mustafa
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Nitsan
authors.initials: N
authors.lastname: Duvdevan
authors.affiliation: Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Meir
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Chaim
authors.initials: C
authors.lastname: Lotan
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers; D002114:Calcinosis; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology*; D006349:Heart Valve Diseases / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D051437:Renal Insufficiency / Q000150:complications*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases