Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment.
BACKGROUND
Glucocorticosteroids (mostly dexamethasone) are widely used to prevent chronic lung disease in premature infants. Neonatal rats treated with dexamethasone have been shown to have reduced cardiac mass and cardiomyocyte hypertrophy, suggesting a lower number of cardiomyocytes at adult age, and a severely reduced life expectancy. In the present study we tested the hypothesis that a lower number of cardiomyocytes in later life is caused by a reduced cardiomyocyte proliferation and/or by early cell death (apoptosis).


RESULTS
Rat pups received dexamethasone or saline control on day 1, 2 and 3 and were sacrificed at day 0, 2, 4, 7 and 21. The cardiomyocytes of dexamethasone treated pups showed a reduced proliferation as indicated by a lower mitotic index and reduced number of Ki-67 positive cardiomyocytes on day 2 and 4 as compared to day 0 and day 7 and also as compared to the age-matched saline pups. On day 7 and day 21 the mitotic index was not different between groups. From day 2 onward up to day 21 dexamethasone treated pups showed a lower number of cardiomyocytes. The cardiomyocytes showed no signs (<<1%) of apoptosis (Caspase-3 and cleaved-PARP) in any group.


CONCLUSIONS
The temporary suppression of cardiomyocyte hyperplasia found in dexamethasone treated pups eventually leads to a reduced number and hypertrophy of cardiomyocytes during adult life.
de Vries
Willem B
WB
Department of Neonatology, University Medical Center Utrecht, Wilhelmina Children's Hospital Roomnr. KE.04.123.1, 85090, 3508 AB, Utrecht, The Netherlands.
Bal
Miriam P
MP
Homoet-van der Kraak
Petra
P
Kamphuis
Patrick J G H
PJ
van der Leij
Feike R
FR
Baan
Jan
J
Steendijk
Paul
P
de Weger
Roel A
RA
van Bel
Frank
F
van Oosterhout
Matthijs F M
MF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000009:adverse effects*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D008297:Male; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone