title: Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy.
abstract: The myocytes of the adult mammalian heart are considered unable to divide. Instead, mitogens induce cardiomyocyte hypertrophy. We have investigated the effect of adenoviral overexpression of cyclin D2 on myocyte proliferation and morphology. Cardiomyocytes in culture were identified by established markers. Cyclin D2 induced DNA synthesis and proliferation of cardiomyocytes and impaired hypertrophy induced by angiotensin II and serum. At the molecular level, cyclin D2 activated CDK4/6 and lead to pRB phosphorylation and downregulation of the cell cycle inhibitors p21Waf1/Cip1 and p27Kip1. Expression of the CDK4/6 inhibitor p16 inhibited proliferation and cyclin D2 overexpressing myocytes became hypertrophic under such conditions. Inhibition of hypertrophy by cyclin D2 correlated with downregulation of p27Kip1. These data show that hypertrophy and proliferation are highly related processes and suggest that cardiomyocyte hypertrophy is due to low amounts of cell cycle activators unable to overcome the block imposed by cell cycle inhibitors. Cell cycle entry upon hypertrophy may be converted to cell division by increased expression of activators such as cyclin D2.
authors.affiliation: Laboratory for Molecular Cardiology and The Heart Centre H:S, Rigshospitalet. 20, Juliane Mariesvej, DK-2100 Copenhagen Ø, Denmark. pkbu@novonordisk.com
authors.forename: Peter K
authors.initials: PK
authors.lastname: Busk
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hinrichsen
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Ane H
authors.initials: AH
authors.lastname: Hansen
authors.forename: Tue E H
authors.initials: TE
authors.lastname: Christoffersen
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049108:Cell Enlargement; D049109:Cell Proliferation; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats
chemical_list: C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D016213:Cyclins; D004247:DNA