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

被引:68
作者
Busk, PK
Bartkova, J
Strom, CC
Wulf-Andersen, L
Hinrichsen, R
Christoffersen, TEH
Latella, L
Bartek, J
Haunso, S
Sheikh, SP
机构
[1] Rigshosp, Lab Mol Kardiol, DK-2100 Copenhagen O, Denmark
[2] Rigshosp, Hjertecenteret HS, DK-2100 Copenhagen O, Denmark
[3] Danish Canc Soc, Dept Cell Cycle & Canc, DK-2100 Copenhagen O, Denmark
关键词
hypertrophy; myocytes; signal transduction; gene expression; protein kinases;
D O I
10.1016/S0008-6363(02)00510-2
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 I inhibited expression of the D-type cyclins and impaired hypertrophic growth induced by angiotensin 11, 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. (C) 2002 Elsevier Science B.V. All rights reserved.
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页码:64 / 75
页数:12
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