title: Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice.
abstract: The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Kato
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Okazaki
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asai
authors.forename: Akio
authors.initials: A
authors.lastname: Hirata
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex