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Published on: September 25, 2017
Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro
Peter K Busk1, Jirina Bartkova, Claes C Strøm
1Laboratoriet for Molekylaer Kardiologi and Hjertecenteret H:S, Rigshospitalet. 20, Juliane Mariesvej., Copenhagen Ø, Denmark. busk@molheart.dk
Insights
D-type cyclins are key regulators in cardiac hypertrophy, a condition leading to heart failure. Their expression and activity increase during hypertrophic growth, suggesting a critical role in this process.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Cardiac hypertrophy, a precursor to heart failure, is influenced by cell-cycle regulatory proteins.
- The specific role of D-type cyclins in cardiac hypertrophy requires further investigation.
Purpose of the Study:
- To investigate the involvement of D-type cyclins in cardiac hypertrophy.
- To determine if D-type cyclins are regulated by hypertrophic stimuli.
Main Methods:
- Studied D-type cyclin expression and kinase activity in rat cardiomyocytes during angiotensin II and pressure overload-induced hypertrophy.
- Manipulated D-type cyclin expression pharmacologically and genetically in neonatal myocytes.
- Utilized differentiation inducing factor 1 to inhibit D-type cyclins and assessed the impact on hypertrophic growth.
Main Results:
- D-type cyclins exhibit low constitutive expression in normal adult myocytes but are upregulated during hypertrophic growth.
- Increased cyclin D expression in vitro mimicked findings in vivo and was induced by various hypertrophic stimuli.
- Inhibition of D-type cyclins impaired hypertrophic growth, which could be rescued by cyclin D2 expression.
Conclusions:
- D-type cyclins are significant regulators of cardiac hypertrophy.
- These findings support the role of cell-cycle regulatory proteins in mediating hypertrophic responses in the heart.
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.
