Ventricular unloading is associated with increased 20s proteasome protein expression in the myocardium.
BACKGROUND
The ubiquitin-proteasome system (UPS) breaks down misfolded and normal proteins, including cell cycle regulatory proteins involved in cardiac hypertrophy. Because congestive heart failure (CHF) increases cardiomyocyte cellular mass, indicative of increased protein synthesis and/or impaired breakdown, and ventricular unloading decreases cardiac hypertrophy and changes regulation of multiple molecular systems ("reverse cardiac remodeling"), we tested the hypothesis that ventricular unloading alters myocardial UPS.


METHODS
In 23 paired myocardial specimens (before and after unloading) ubiquitin, 20S proteasome, and cyclin D1 were investigated immunohistochemically and morphometrically quantified in relation to cardiomyocyte hypertrophy, DNA content, nuclear profile area and perimeter, and cyclin D1 protein expression. Moreover, 20S proteasome plasma concentrations were measured by enzyme-linked immunoassay (ELISA).


RESULTS
In CHF, sarcoplasmic 20S proteasome protein expression was significantly decreased compared with controls, but significantly increased after unloading. In contrast, sarcoplasmic ubiquitin protein was increased in CHF but significantly decreased after unloading, and both variables were inversely correlated. Cardiomyocyte 20S proteasome expression correlated inversely with cell size, mean DNA content, and cyclin D1, whereas ubiquitin protein expression was positively correlated with these parameters. The 20S proteasome plasma concentration was significantly increased after unloading.


CONCLUSIONS
Our data indicate that: (1) the UPS is depressed in CHF; and (2) this is reversed by ventricular unloading and associated with decreased cardiomyocyte hypertrophy, mean DNA content, and cell cycle regulatory proteins. The findings support the view that the UPS is involved in both the pathogenesis of cardiac hypertrophy and "reverse cardiac remodeling" after ventricular unloading.
Wohlschlaeger
Jeremias
J
Department of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
Sixt
Stephan Urs
SU
Stoeppler
Tatjana
T
Schmitz
Klaus Jürgen
KJ
Levkau
Bodo
B
Tsagakis
Konstantinos
K
Vahlhaus
Christian
C
Schmid
Christof
C
Peters
Jürgen
J
Schmid
Kurt Werner
KW
Milting
Hendrik
H
Baba
Hideo Andreas
HA
D000293:Adolescent; D000328:Adult; D002467:Cell Nucleus / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000601:surgery*; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D020257:Ventricular Remodeling; D055815:Young Adult
D025801:Ubiquitin; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex