Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro.
OBJECTIVE
Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Present knowledge suggests that cell-cycle regulatory proteins take part in hypertrophy. We have investigated if the D-type cyclins are involved in cardiac hypertrophy.


METHODS
The expression and activity of the D-type cyclins and associated kinases in cardiomyocytes were studied during angiotensin II- and pressure overload-induced hypertrophy in rats (Rattus norvegicus) and in isolated, neonatal cardiomyocytes. Expression of the D-type cyclins was manipulated pharmacologically and genetically in neonatal myocytes.


RESULTS
In the left ventricle, there was a low, constitutive expression of the D-type cyclins, which may have a biological role in normal, adult myocytes. The protein level and the associated kinase activity of the D-type cyclins were up-regulated during hypertrophic growth. The increase in cyclin D expression could be mimicked in vitro in neonatal cardiac myocytes. Interestingly, the cyclin Ds were up-regulated by hypertrophic elicitors that stimulate different signalling pathways, suggesting that cyclin D expression is an inherent part of cardiac hypertrophy. Treatment of myocytes with the compound differentiation inducing factor 1 inhibited expression of the D-type cyclins and impaired hypertrophic growth induced by angiotensin II, phenylephrine and serum. The response to hypertrophic elicitors could be restored in differentiation inducing factor 1-treated myocytes by expressing cyclin D2 from a heterologous promoter.


CONCLUSIONS
Our results point to the D-type cyclins as important regulators of cardiac hypertrophy. This supports the notion that cell-cycle regulatory proteins regulate hypertrophic growth.
Busk
Peter K
PK
Laboratoriet for Molekylaer Kardiologi and Hjertecenteret H:S, Rigshospitalet. 20, Juliane Mariesvej., Copenhagen Ø, Denmark. busk@molheart.dk
Bartkova
Jirina
J
Strøm
Claes C
CC
Wulf-Andersen
Linda
L
Hinrichsen
Rebecca
R
Christoffersen
Tue E H
TE
Latella
Lucia
L
Bartek
Jiri
J
Haunsø
Stig
S
Sheikh
Søren P
SP
D000804:Angiotensin II; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056742:Cyclin D2; D056743:Cyclin D3; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000378:metabolism; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D015801:Helminth Proteins / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C486197:Ccnd2 protein, rat; C534698:Ccnd3 protein, rat; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D015801:Helminth Proteins; D000804:Angiotensin II; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases