Ubiquitin-Like Protein ISG15 (Interferon-Stimulated Gene of 15 kDa) in Host Defense Against Heart Failure in a Mouse Model of Virus-Induced Cardiomyopathy
| Autor: | Philipp Bleienheuft, Konstantinos Savvatis, Wolfgang Poller, Lars Ketscher, Nicola L. Diny, Dorota Respondek, Carsten Tschöpe, Antje Voigt, Anika Lindner, Elisa Opitz, Nadine Althof, Martina Sauter, Anna Rahnefeld, Karin Klingel, Anett Schuermann, Klaus-Peter Knobeloch, Ulrike Seifert |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Cardiomyopathy Dilated Male Viral cardiomyopathy Myocarditis Biopsy T-Lymphocytes viruses Cardiomyopathy Coxsackievirus Infections Biology Virus Replication Virus Viral Proteins Physiology (medical) medicine Animals Humans Myocytes Cardiac Ubiquitins Heart Failure Interferon-stimulated gene Middle Aged medicine.disease ISG15 Virology Immunity Innate Enterovirus B Human Killer Cells Natural Mice Inbred C57BL Cysteine Endopeptidases Disease Models Animal Viral replication Cytokines Female Cardiology and Cardiovascular Medicine Ubiquitin-Like Protein ISG15 |
| Zdroj: | Circulation. 130:1589-1600 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.114.009847 |
| Popis: | Background— Common causative agents in the development of inflammatory cardiomyopathy include cardiotropic viruses such as coxsackievirus B3 (CVB3). Here, we investigated the role of the ubiquitin-like modifier interferon-stimulated gene of 15 kDa (ISG15) in the pathogenesis of viral cardiomyopathy. Methods and Results— In CVB3-infected mice, the absence of protein modification with ISG15 was accompanied by a profound exacerbation of myocarditis and by a significant increase in mortality and heart failure. We found that ISG15 in cardiomyocytes contributed significantly to the suppression of viral replication. In the absence of an intact ISG15 system, virus titers were markedly elevated by postinfection day 8, and viral RNA persisted in ISG15 −/− mice at postinfection day 28. Ablation of the ISG15 protein modification system in CVB3 infection predisposed mice to long-term disease with deposition of collagen fibers, all leading to inflammatory cardiomyopathy. We found that ISG15 acts as part of the intrinsic immunity in cardiomyocytes and detected no significant effects of ISG15 modification on the cellular immune response. ISG15 modification of CVB3 2A protease counterbalanced CVB3-induced cleavage of the host cell eukaryotic initiation factor of translation eIF4G in cardiomyocytes, thereby counterbalancing the shutoff of host cell translation in CVB3 infection. We demonstrate that ISG15 suppressed infectious virus yield in human cardiac myocytes and the induction of ISG15 in patients with viral cardiomyopathy. Conclusions— The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. Interference with the ISG15 system might be a novel therapeutic approach in viral cardiomyopathy. |
| Databáze: | OpenAIRE |
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