title: Survivin determines cardiac function by controlling total cardiomyocyte number.
abstract: BACKGROUND
  Survivin inhibits apoptosis and regulates cell division in many organs, but its function in the heart is unknown.
  
  
  RESULTS
  We show that cardiac-specific deletion of survivin resulted in premature cardiac death. The underlying cause was a dramatic reduction in total cardiomyocyte numbers as determined by a stereological method for quantification of cells per organ. The resulting increased hemodynamic load per cell led to progressive heart failure as assessed by echocardiography, magnetic resonance imaging, positron emission tomography, and invasive catheterization. The reduction in total cardiomyocyte number in alpha-myosin heavy chain (MHC)-survivin(-/-) mice was due to an approximately 50% lower mitotic rate without increased apoptosis. This occurred at the expense of DNA accumulation because survivin-deficient cardiomyocytes displayed marked DNA polyploidy indicative of consecutive rounds of DNA replication without cell division. Survivin small interfering RNA knockdown in neonatal rat cardiomyocytes also led to polyploidization and cell cycle arrest without apoptosis. Adenoviral overexpression of survivin in cardiomyocytes inhibited doxorubicin-induced apoptosis, induced DNA synthesis, and promoted cell cycle progression. The phenotype of the alphaMHC-survivin(-/-) mice also allowed us to determine the minimum cardiomyocyte number sufficient for normal cardiac function. In human cardiomyopathy, survivin was potently induced in the failing heart and downregulated again after hemodynamic support by a left ventricular assist device. Its expression positively correlated with the mean cardiomyocyte DNA content.
  
  
  CONCLUSIONS
  We suggest that the ontogenetically determined cardiomyocyte number may be an independent factor in the susceptibility to cardiac diseases. Through its profound impact on both cardiomyocyte replication and apoptosis, survivin may emerge as a promising new target for myocardial regeneration.
authors.affiliation: Institut für Pathophysiologie, Universitätsklinikum Essen, Essen Germany. levkau@uni-essen.de
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Karin
authors.initials: K
authors.lastname: von Wnuck Lipinski
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Naomasa
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Lars
authors.initials: L
authors.lastname: Stegger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.forename: Jens
authors.initials: J
authors.lastname: Fischer
authors.forename: Patrick
authors.initials: P
authors.lastname: Hsieh
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Ou
authors.forename: Felix
authors.initials: F
authors.lastname: Mehrhof
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.forename: Marek
authors.initials: M
authors.lastname: Matus
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
mesh_terms: D000818:Animals; D002452:Cell Count; D048429:Cell Size; D002478:Cells, Cultured; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology*; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D012097:Repressor Proteins; D000077022:Survivin; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000077022:Survivin