© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro
aLaboratoriet for Molekylær Kardiologi and Hjertecenteret H:S, Rigshospitalet. 20, Juliane Mariesvej., DK-2100 Copenhagen Ø, Denmark
bDepartment of Cell Cycle and Cancer, Danish Cancer Society, 49, Strandboulevarden, DK-2100 Copenhagen Ø, Denmark
* Corresponding author. Tel.: +45-3545-6737; fax: +45-3545-6500 busk{at}molheart.dk
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. Conclusion: 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.
KEYWORDS Hypertrophy; Myocytes; Signal transduction; Gene expression; Protein kinases
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