The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury

Hideo Yasukawa, Toshitaka Yajima, Hervé Duplain, Mitsuo Iwatate, Masakuni Kido, Masahiko Hoshijima, Matthew D. Weitzman, Tomoyuki Nakamura, Sarah Woodard, Dingding Xiong, Akihiko Yoshimura, Kenneth R. Chien, Kirk U. Knowlton

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90 Citations (Scopus)

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 endorgan damage during the early stages of infection.

Original languageEnglish
Pages (from-to)469-478
Number of pages10
JournalJournal of Clinical Investigation
Volume111
Issue number4
DOIs
Publication statusPublished - 2003 Feb
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Yasukawa, H., Yajima, T., Duplain, H., Iwatate, M., Kido, M., Hoshijima, M., Weitzman, M. D., Nakamura, T., Woodard, S., Xiong, D., Yoshimura, A., Chien, K. R., & Knowlton, K. U. (2003). The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. Journal of Clinical Investigation, 111(4), 469-478. https://doi.org/10.1172/JCI16491