Reversible regulation of the retinoblastoma protein/E2F-1 pathway during "reverse cardiac remodelling" after ventricular unloading.
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.


CONCLUSIONS
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.
Wohlschlaeger
Jeremias
J
Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Schmitz
Klaus Jürgen
KJ
Takeda
Atsushi
A
Takeda
Nobuakira
N
Vahlhaus
Christian
C
Stypmann
Jörg
J
Schmid
Christof
C
Baba
Hideo Andreas
HA
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D006984:Hypertrophy; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*; D055815:Young Adult
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D019938:Cyclin D1