title: The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury.
abstract: Enteroviral infections of the heart are among the most commonly identified causes of acute myocarditis in children and adults and have been implicated in dilated cardiomyopathy. Although there is considerable information regarding the cellular immune response in myocarditis, little is known about innate signaling mechanisms within the infected cardiac myocyte that contribute to the host defense against viral infection. Here we show the essential role of Janus kinase (JAK) signaling in cardiac myocyte antiviral defense and a negative role of an intrinsic JAK inhibitor, the suppressor of cytokine signaling (SOCS), in the early disease process. Cardiac myocyte-specific transgenic expression of SOCS1 inhibited enterovirus-induced signaling of JAK and the signal transducers and activators of transcription (STAT), with accompanying increases in viral replication, cardiomyopathy, and mortality in coxsackievirus-infected mice. Furthermore, the inhibition of SOCS in the cardiac myocyte through adeno-associated virus-mediated (AAV-mediated) expression of a dominant-negative SOCS1 increased the myocyte resistance to the acute cardiac injury caused by enteroviral infection. These results indicate that strategies directed at inhibition of SOCS in the heart and perhaps other organs can augment the host-cell antiviral system, thus preventing viral-mediated end-organ damage during the early stages of infection.
authors.affiliation: Institute of Molecular Medicine, Department of Medicine, and. Division of Cardiothoracic Surgery, University of California at San Diego, La Jolla, California 92093-0613, USA.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.forename: Hervé
authors.initials: H
authors.lastname: Duplain
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iwatate
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kido
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Weitzman
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Sarah
authors.initials: S
authors.lastname: Woodard
authors.forename: Dingding
authors.initials: D
authors.lastname: Xiong
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D029822:Enterovirus B, Human / Q000472:pathogenicity / Q000502:physiology; D004769:Enterovirus Infections / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009205:Myocarditis / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014779:Virus Replication
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases