cyclin-d1 and Hypertrophy--Left-Ventricular

Mechanical support in congestive heart failure (CHF) by a left ventricular assist device (LVAD) is associated with decreased cardiac hypertrophy and altered cardiomyocyte molecular pathways. Survivin initiates cell cycle progression by increased cyclinD1/cdk4 complexes by abrogation of the inhibitory effect of p16(INK4a) on cdk4. Accordingly, the role of survivin in CHF and after unloading was explored.. In 20 myocardial samples from patients with terminal CHF (before and after LVAD), the protein expression of survivin, cyclin D1, cdk4, p16(INK4a), and proliferating cell nuclear antigen (PCNA) was immunohistochemically investigated and morphometrically quantified by calculating the percentage of positive cardiomyocytes per visual field. These data were correlated with cardiomyocyte size and DNA content.. The mean percentage of cardiomyocytes immunoreactive against survivin, cyclin D1, cdk4, p16(INK4a), and PCNA was significantly increased in CHF compared with controls and significantly decreased after unloading (57.6% to 26.6%, 42% to 18.3%, 45.4% to 15.3%, 73.0% to 60.5%, and 43.5% to 25.2%, respectively; p < 0.05). All investigated parameters, in particular survivin and cyclin D1, significantly correlated with cardiomyocyte diameters (r = 0.405; r = 0.563) and DNA content (r = 0.430; r = 0.480), both in CHF (cardiac remodelling) and after unloading (p < 0.05).. These data indicate that survivin is reversibly regulated by ventricular unloading and might be involved in cell size/DNA content regulation and cardiomyocyte proliferation in cardiac remodelling during CHF. It is suggested that after ventricular unloading, decreased survivin protein expression might contribute to cardiac hypertrophy decrease by lowering the number of cyclin D1/cdk4 complexes.

Topics: Adolescent; Adult; Cell Cycle; Cell Size; Child; Child, Preschool; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p16; DNA; Female; Heart Failure; Heart-Assist Devices; Humans; Hypertrophy, Left Ventricular; Inhibitor of Apoptosis Proteins; Male; Microtubule-Associated Proteins; Middle Aged; Myocytes, Cardiac; Proliferating Cell Nuclear Antigen; Retrospective Studies; Survivin; Ventricular Remodeling; Young Adult

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.. 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.. 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.. 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.

Topics: Angiotensin II; Animals; Blotting, Western; Caenorhabditis elegans Proteins; Carrier Proteins; Cells, Cultured; Cyclin D1; Cyclin D2; Cyclin D3; Cyclin-Dependent Kinases; Cyclins; Helminth Proteins; Hypertrophy, Left Ventricular; Myocytes, Cardiac; Rats; Rats, Wistar; Signal Transduction