title: The imbalance between proliferation and apoptosis contributes to degeneration of aortic valves and bioprostheses.
abstract: BACKGROUND
  The pathomechanisms underlying aortic valve degeneration are incompletely understood. Therefore, the aim of our work was to assess the quantitative changes of proliferation and apoptosis accompanied by cellular phenotype alternations and matrix secretionin aortic sclerotic and stenotic valves and degenerative bioprostheses, as well as to detect the expression pattern of the rapamycin receptor FKBP12 across these three valve types.
  
  
  METHODS
  Mild-to-moderate sclerotic and stenotic valves and degenerative bioprostheses from 30 patients (n = 10 per group) were collected at autopsy or by surgery. Ki67+, FKBP12+, alpha-actin+, HSP47+ and TUNEL+ apoptotic cells were analyzed by immunohistochemistry.
  
  
  RESULTS
  The main finding was the reduced proliferation and increased apoptosis in stenotic valves (ST) compared to the sclerotic ones (SC) (proliferation: ST: 20.8 ± 2.0% vs. SC: 30.1 ±2.2%, apoptosis: ST: 40.7 ± 5.0% vs. SC: 28.0 ± 5.1%, p < 0.05, respectively). Analogical alternations were found in degenerative bioprostheses (BP) (proliferation: 4.8 ± 2.3%; apoptosis: 13.1 ± 6.8%). Corresponding changes were observed in the valve cellularity (ST: 893 ± 168, SC: 1034 ± 284, BP: 385 ± 179 cells/mm2, p < 0.05, respectively). The FKBP12 signaling was reduced in diseased valves and bioprostheses (ST: 28.1 ± 3.6%, SC: 42.2 ± 3.8%, BP: 5.8 ± 1.9%, p < 0.05, respectively). Further, the augmented alpha-actin expressionwas observed as the degenerative process progressed (ST: 30.3 ± 5.0%, SC: 22.6 ± 2.7%, BP:8.7 ± 4.0%, p < 0.05, respectively), followed by the upregulation of HSP47 (ST: 22.6 ± 2.8%,SC: 15.4 ± 2.1%, BP: 3.4 ± 1.0%, p < 0.05, respectively) and consecutive matrix accumulation.
  
  
  CONCLUSIONS
  The imbalance between proliferation and apoptosis with cellular phenotypical shift and subsequent matrix secretion may contribute to aortic valve stenosis and bioprosthesis degeneration. The identification of FKBP12 expression may implicate potential therapeutic strategies.
authors.affiliation: Department of Internal Medicine II - Cardiology, Angiology and Pulmonology, University of Bonn, Germany. Izabela.Tuleta@ukb.uni-bonn.de.
authors.forename: Izabela
authors.initials: I
authors.lastname: Tuleta
authors.forename: Abdel Karim
authors.initials: AK
authors.lastname: Al Ghaddioui
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauriedel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wernert
authors.forename: Claus Jürgen
authors.initials: CJ
authors.lastname: Preusse
authors.forename: Armin
authors.initials: A
authors.lastname: Welz
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Dirk
authors.initials: D
authors.lastname: Skowasch
mesh_terms: D000199:Actins / Q000032:analysis; D000368:Aged; D001021:Aortic Valve / Q000737:chemistry / Q000473:pathology* / Q000601:surgery*; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D017209:Apoptosis; D001344:Autopsy; D015415:Biomarkers / Q000032:analysis; D001705:Bioprosthesis; D049109:Cell Proliferation; D005260:Female; D005355:Fibrosis; D050958:HSP47 Heat-Shock Proteins / Q000032:analysis; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation / Q000009:adverse effects / Q000295:instrumentation*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D011474:Prosthesis Design; D011475:Prosthesis Failure; D012720:Severity of Illness Index; D022061:Tacrolimus Binding Protein 1A / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D000199:Actins; D015415:Biomarkers; D050958:HSP47 Heat-Shock Proteins; D019394:Ki-67 Antigen; C494660:SERPINH1 protein, human; D022061:Tacrolimus Binding Protein 1A