Different regulation of p27 and Akt during cardiomyocyte proliferation and hypertrophy.
Postnatal cardiomyocytes normally grow by hypertrophy but show a limited proliferate response to certain stimuli. Although the proliferative capacity declines shortly after birth, neonatal cardiomyocytes can grow both by hypertrophy and by proliferation. Therefore, we have used neonatal cardiomyocytes to investigate the molecular differences between hypertrophic and proliferative growth of cardiomyocytes. Stimulation of neonatal cardiomyocytes with angiotensin II mainly induced hypertrophy, whereas PDGF only had a minor effect on the size of the myocytes. In contrast, PDGF induced significant proliferation in the cardiomyocyte cultures whereas angiotensin II treatment only resulted in a small increase in the number of cells. Measurement of cyclin D-dependent kinase specific phosphorylation of pRb by immunohistochemistry showed that, both stimuli activate the G1 phase of the cell cycle. By western blotting we found that PDGF-induced proliferation correlates with activation of Akt, inactivation of GSK-3beta and downregulation of the cyclin-dependent kinase inhibitor p27, whereas angiotensin II only had a small effect on Akt, GSK-3beta and p27. Our data support the hypothesis that, the hypertrophic and proliferative responses are both activated by G1 cell cycle molecules. The difference between the two responses appears to be that high amounts of p27 are present during hypertrophic growth, whereas proliferation involves downregulation of p27 and GSK-3beta activity and upregulation of Akt.
Hinrichsen
Rebecca
R
Cell Biology, Biosystems Department, Risø National Laboratory, DK-4000 Roskilde, Denmark. r.hinrichsen@jubii.dk
Haunsø
Stig
S
Busk
Peter K
PK
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006984:Hypertrophy; D007150:Immunohistochemistry; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D010982:Platelet-Derived Growth Factor; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3