Survivin determines cardiac function by controlling total cardiomyocyte number.
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.
Levkau
Bodo
B
Institut für Pathophysiologie, Universitätsklinikum Essen, Essen Germany. levkau@uni-essen.de
Schäfers
Michael
M
Wohlschlaeger
Jeremias
J
von Wnuck Lipinski
Karin
K
Keul
Petra
P
Hermann
Sven
S
Kawaguchi
Naomasa
N
Kirchhof
Paulus
P
Fabritz
Larissa
L
Stypmann
Jörg
J
Stegger
Lars
L
Flögel
Ulrich
U
Schrader
Jürgen
J
Fischer
Jens W
JW
Fischer
Jens
J
Hsieh
Patrick
P
Ou
Yen-Ling
YL
Mehrhof
Felix
F
Tiemann
Klaus
K
Ghanem
Alexander
A
Matus
Marek
M
Neumann
Joachim
J
Heusch
Gerd
G
Schmid
Kurt W
KW
Conway
Edward M
EM
Baba
Hideo A
HA
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
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