Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro

doi:10.1016/S0008-6363(02)00510-2

Cardiovascular Research 2002 56(1):64-75; doi:10.1016/S0008-6363(02)00510-2
© 2002 by European Society of Cardiology

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Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro

Peter K Busk^a^,*, Jirina Bartkova^b, Claes C Strøm^a, Linda Wulf-Andersen^a, Rebecca Hinrichsen^a, Tue E.H Christoffersen^a, Lucia Latella^b, Jiri Bartek^b, Stig Haunsø^a and Søren P Sheikh^a

^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 stimuliand can lead to cardiomyopathy and heart failure. Present knowledgesuggests that cell-cycle regulatory proteins take part in hypertrophy.We have investigated if the D-type cyclins are involved in cardiachypertrophy. Methods: The expression and activity of the D-typecyclins and associated kinases in cardiomyocytes were studiedduring angiotensin II- and pressure overload-induced hypertrophyin rats (Rattus norvegicus) and in isolated, neonatal cardiomyocytes.Expression of the D-type cyclins was manipulated pharmacologicallyand 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 theD-type cyclins were up-regulated during hypertrophic growth.The increase in cyclin D expression could be mimicked in vitroin neonatal cardiac myocytes. Interestingly, the cyclin Ds wereup-regulated by hypertrophic elicitors that stimulate differentsignalling pathways, suggesting that cyclin D expression isan inherent part of cardiac hypertrophy. Treatment of myocyteswith the compound differentiation inducing factor 1 inhibitedexpression of the D-type cyclins and impaired hypertrophic growthinduced by angiotensin II, phenylephrine and serum. The responseto hypertrophic elicitors could be restored in differentiationinducing factor 1-treated myocytes by expressing cyclin D2 froma heterologous promoter. Conclusion: Our results point to theD-type cyclins as important regulators of cardiac hypertrophy.This supports the notion that cell-cycle regulatory proteinsregulate hypertrophic growth.

KEYWORDS Hypertrophy; Myocytes; Signal transduction; Gene expression; Protein kinases

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