title: Cardiomyocyte survivin protein expression is associated with cell size and DNA content in the failing human heart and is reversibly regulated after ventricular unloading.
abstract: BACKGROUND
  Mechanical support in congestive heart failure (CHF) by a left ventricular assist device (LVAD) is associated with decreased cardiac hypertrophy and altered cardiomyocyte molecular pathways. Survivin initiates cell cycle progression by increased cyclinD1/cdk4 complexes by abrogation of the inhibitory effect of p16(INK4a) on cdk4. Accordingly, the role of survivin in CHF and after unloading was explored.
  
  
  METHODS
  In 20 myocardial samples from patients with terminal CHF (before and after LVAD), the protein expression of survivin, cyclin D1, cdk4, p16(INK4a), and proliferating cell nuclear antigen (PCNA) was immunohistochemically investigated and morphometrically quantified by calculating the percentage of positive cardiomyocytes per visual field. These data were correlated with cardiomyocyte size and DNA content.
  
  
  RESULTS
  The mean percentage of cardiomyocytes immunoreactive against survivin, cyclin D1, cdk4, p16(INK4a), and PCNA was significantly increased in CHF compared with controls and significantly decreased after unloading (57.6% to 26.6%, 42% to 18.3%, 45.4% to 15.3%, 73.0% to 60.5%, and 43.5% to 25.2%, respectively; p < 0.05). All investigated parameters, in particular survivin and cyclin D1, significantly correlated with cardiomyocyte diameters (r = 0.405; r = 0.563) and DNA content (r = 0.430; r = 0.480), both in CHF (cardiac remodelling) and after unloading (p < 0.05).
  
  
  CONCLUSIONS
  These data indicate that survivin is reversibly regulated by ventricular unloading and might be involved in cell size/DNA content regulation and cardiomyocyte proliferation in cardiac remodelling during CHF. It is suggested that after ventricular unloading, decreased survivin protein expression might contribute to cardiac hypertrophy decrease by lowering the number of cyclin D1/cdk4 complexes.
authors.affiliation: Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Birgit
authors.initials: B
authors.lastname: Meier
authors.forename: Klaus Jürgen
authors.initials: KJ
authors.lastname: Schmitz
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
authors.forename: Nobuakira
authors.initials: N
authors.lastname: Takeda
authors.forename: Christian
authors.initials: C
authors.lastname: Vahlhaus
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Christof
authors.initials: C
authors.lastname: Schmid
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.forename: Hideo Andreas
authors.initials: HA
authors.lastname: Baba
mesh_terms: D000293:Adolescent; D000328:Adult; D002453:Cell Cycle / Q000502:physiology; D048429:Cell Size; D002648:Child; D002675:Child, Preschool; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006353:Heart-Assist Devices; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012189:Retrospective Studies; D000077022:Survivin; D020257:Ventricular Remodeling / Q000502:physiology; D055815:Young Adult
chemical_list: C107489:BIRC5 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D018809:Proliferating Cell Nuclear Antigen; D000077022:Survivin; D019938:Cyclin D1; D004247:DNA; D051358:Cyclin-Dependent Kinase 4