RATIONALE: Ubiquitin-proteasome system (UPS) dysfunction has been implicated in 
cardiac pathogenesis. Understanding how cardiac UPS function is regulated will 
facilitate delineating the pathophysiological significance of UPS dysfunction 
and developing new therapeutic strategies. The COP9 (constitutive 
photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this 
has not been tested in a critical vertebrate organ. Moreover, the role of CSN in 
a postmitotic organ and the impact of cardiomyocyte-restricted UPS dysfunction 
on the heart have not been reported.
OBJECTIVE: We sought to determine the role of CSN-mediated deneddylation in UPS 
function and postnatal cardiac development and function.
METHODS AND RESULTS: Cardiomyocyte-restricted Csn8 gene knockout (CR-Csn8KO) in 
mice was achieved using a Cre-LoxP system. CR-Csn8KO impaired CSN holocomplex 
formation and cullin deneddylation and resulted in decreases in F-box proteins. 
Probing with a surrogate misfolded protein revealed severe impairment of UPS 
function in CR-Csn8KO hearts. Consequently, CR-Csn8KO mice developed cardiac 
hypertrophy, which rapidly progressed to heart failure and premature death. 
Massive cardiomyocyte necrosis rather than apoptosis appears to be the primary 
cause of the heart failure. This is because (1) massive necrotic cell death and 
increased infiltration of leukocytes were observed before increased apoptosis; 
(2) increased apoptosis was not detectable until overt heart failure was 
observed; and (3) cardiac overexpression of Bcl2 failed to ameliorate CR-Csn8KO 
mouse premature death.
CONCLUSIONS: Csn8/CSN plays an essential role in cullin deneddylation, 
UPS-mediated degradation of a subset of proteins, and the survival of 
cardiomyocytes and, therefore, is indispensable in postnatal development and 
function of the heart. Cardiomyocyte-restricted UPS malfunction can cause heart 
failure.