Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice

Huabo Su, Jie Li, Suchithra Menon, Jinbao Liu, Asangi R. Kumarapeli, Ning Wei, Xuejun Wang

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)40-50
Number of pages11
JournalCirculation Research
Volume108
Issue number1
DOIs
StatePublished - Jan 7 2011

Fingerprint

Cullin Proteins
Dilated Cardiomyopathy
Proteasome Endopeptidase Complex
Ubiquitin
Cardiac Myocytes
Necrosis
Gene Knockout Techniques
Heart Failure
Knockout Mice
Premature Mortality
Apoptosis
F-Box Proteins
Cardiomegaly
Vertebrates
Proteins
Leukocytes
Cell Death

Keywords

  • COP9 signalosome
  • Cell death
  • Heart failure
  • Proteasome
  • Ubiquitin E3 ligases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice. / Su, Huabo; Li, Jie; Menon, Suchithra; Liu, Jinbao; Kumarapeli, Asangi R.; Wei, Ning; Wang, Xuejun.

In: Circulation Research, Vol. 108, No. 1, 07.01.2011, p. 40-50.

Research output: Contribution to journalArticle

@article{7e401b2794074b9b9097088ca930739f,
title = "Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice",
abstract = "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.",
keywords = "COP9 signalosome, Cell death, Heart failure, Proteasome, Ubiquitin E3 ligases",
author = "Huabo Su and Jie Li and Suchithra Menon and Jinbao Liu and Kumarapeli, {Asangi R.} and Ning Wei and Xuejun Wang",
year = "2011",
month = "1",
day = "7",
doi = "10.1161/CIRCRESAHA.110.230607",
language = "English (US)",
volume = "108",
pages = "40--50",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice

AU - Su, Huabo

AU - Li, Jie

AU - Menon, Suchithra

AU - Liu, Jinbao

AU - Kumarapeli, Asangi R.

AU - Wei, Ning

AU - Wang, Xuejun

PY - 2011/1/7

Y1 - 2011/1/7

N2 - 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.

AB - 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.

KW - COP9 signalosome

KW - Cell death

KW - Heart failure

KW - Proteasome

KW - Ubiquitin E3 ligases

UR - http://www.scopus.com/inward/record.url?scp=79451475816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79451475816&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.110.230607

DO - 10.1161/CIRCRESAHA.110.230607

M3 - Article

C2 - 21051661

AN - SCOPUS:79451475816

VL - 108

SP - 40

EP - 50

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 1

ER -