Proteasome inhibition attenuates coxsackievirus-induced myocardial damage in mice.

TitleProteasome inhibition attenuates coxsackievirus-induced myocardial damage in mice.
Publication TypeJournal Article
Year of Publication2008
AuthorsGao, G, Zhang, J, Si, X, Wong, J, Cheung, C, McManus, B, Luo, H
JournalAm J Physiol Heart Circ Physiol
Volume295
Issue1
PaginationH401-8
Date Published2008 Jul
ISSN0363-6135
KeywordsAnimals, Antiviral Agents, Blotting, Western, Capsid Proteins, Cell Line, Coxsackievirus Infections, Disease Models, Animal, Dose-Response Relationship, Drug, Enterovirus B, Human, Immunohistochemistry, Injections, Subcutaneous, Male, Mice, Mice, Inbred A, Myocarditis, Myocytes, Cardiac, Protease Inhibitors, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Time Factors, Ubiquitin, Ubiquitin-Activating Enzymes, Ubiquitin-Conjugating Enzymes, Viral Plaque Assay
Abstract

Coxsackievirus B3 (CVB3) is one of the most prevalent pathogens of viral myocarditis, which may persist chronically and progress to dilated cardiomyopathy. We previously demonstrated a critical role of the ubiquitin-proteasome system (UPS) in the regulation of coxsackievirus replication in mouse cardiomyocytes. In the present study, we extend our interest to an in vivo animal model to examine the regulation and role of the UPS in CVB3-induced murine myocarditis. Male myocarditis-susceptible A/J mice at age 4-5 wk were randomized to four groups: sham infection + vehicle (n = 10), sham infection + proteasome inhibitor (n = 10), virus + vehicle (n = 20), and virus + proteasome inhibitor (n = 20). Proteasome inhibitor was administered subcutaneously once a day for 3 days. Mice were killed on day 9 after infection, and infected hearts were harvested for Western blot analysis, plaque assay, immunostaining, and histological examination. We showed that CVB3 infection led to an accumulation of ubiquitin conjugates at 9 days after infection. Protein levels of ubiquitin-activating enzyme E1A/E1B, ubiquitin-conjugating enzyme UBCH7, as well as deubiquitinating enzyme UCHL1 were markedly increased in CVB3-infected mice compared with sham infection. However, there was no significant alteration in proteasome activities at 9 days after infection. Immunohistochemical staining revealed that increased expression of E1A/E1B was mainly localized to virus-damaged cells. Finally, we showed that application of a proteasome inhibitor significantly reduced CVB3-induced myocardial damage. This observation reveals a novel mechanism of coxsackieviral pathogenesis, and suggests that the UPS may be an attractive therapeutic target against coxsackievirus-induced myocarditis.

DOI10.1152/ajpheart.00292.2008
Alternate JournalAm. J. Physiol. Heart Circ. Physiol.
PubMed ID18515649
PubMed Central IDPMC2494750