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Published on: June 3, 2018
Reversible regulation of the retinoblastoma protein/E2F-1 pathway during "reverse cardiac remodelling" after
Jeremias Wohlschlaeger1, Klaus Jürgen Schmitz, Atsushi Takeda
1Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Background:
Cyclin D1, the retinoblastoma (Rb) protein, and the E2F transcription factors are involved in the pathogenesis of cardiac hypertrophy. Cyclin D1/cdk4 complexes, by phosphorylation, inactivate Rb, thereby abrogating its growth-inhibitory effect. Ventricular unloading is associated with reversible regulation of numerous cardiomyocyte molecular systems and decreased hypertrophy. Accordingly, the hypothesis whether the Rb/E2F-1 pathway is altered by ventricular unloading was tested, and correlations with the cyclin D1 protein expression and cardiomyocyte diameters were explored.
Methods:
In 21 paired myocardial samples (before and after unloading) from patients with congestive heart failure (CHF), cyclin D1, phosphorylated Rb (pRb), its homologues p107 and p130 (pocket proteins), and E2F-1 were immunohistochemically investigated and morphometrically quantified. Cardiomyocyte diameters were morphometrically determined.
Results:
Cyclin D1 and the proteins of the Rb/E2F-1 pathway were significantly increased during CHF compared with controls and were significantly decreased after unloading. Cyclin D1, pRb, and p130 protein expression correlated significantly with cardiomyocyte diameters. A significant positive correlation was noted between the pocket proteins, E2F-1, and cyclin D1.
Conclusion:
Increased protein expression of phosphorylated (inactivated) Rb and the pocket proteins is associated with cardiomyocyte hypertrophy in CHF. Rb inactivation might be explained by phosphorylation by increased numbers of cyclin D1/cdk4 complexes associated with cardiomyocyte hypertrophy. However, ventricular unloading can reversibly regulate this process. These data underscore the importance of cell cycle regulatory proteins in the pathogenesis of CHF-associated (maladaptive) cardiomyocyte hypertrophy and might offer novel clues for pharmacologic approaches of congestive heart failure.
Insights
Ventricular unloading reversed increased cyclin D1 and Rb/E2F-1 pathway proteins in heart failure, reducing cardiomyocyte size. This highlights cell cycle regulators
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Cycle Regulation
Background:
- Cardiac hypertrophy involves Cyclin D1, retinoblastoma (Rb) protein, and E2F transcription factors.
- Cyclin D1/cdk4 complexes inactivate Rb, promoting hypertrophy.
- Ventricular unloading reduces cardiac hypertrophy and alters cardiomyocyte molecular systems.
Purpose of the Study:
- To investigate alterations in the Rb/E2F-1 pathway during ventricular unloading.
- To explore correlations between this pathway, cyclin D1 expression, and cardiomyocyte size.
Main Methods:
- Immunohistochemistry and morphometric quantification of cyclin D1, pRb, p107, p130, and E2F-1 in 21 paired myocardial samples from heart failure patients (before and after unloading).
- Measurement of cardiomyocyte diameters.
Main Results:
- Proteins of the Rb/E2F-1 pathway and cyclin D1 were elevated in heart failure and decreased after unloading.
- Cyclin D1, pRb, and p130 expression correlated with cardiomyocyte diameters.
- Positive correlations were observed between pocket proteins, E2F-1, and cyclin D1.
Conclusions:
- Elevated phosphorylated Rb and pocket proteins are linked to cardiomyocyte hypertrophy in heart failure.
- Increased cyclin D1/cdk4 complexes likely contribute to Rb inactivation and hypertrophy.
- Ventricular unloading can reversibly modulate these cell cycle regulators, offering therapeutic insights for heart failure.
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