The suppressor of cytokine signaling–1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury
Hideo Yasukawa, … , Kenneth R. Chien, Kirk U. Knowlton
Hideo Yasukawa, … , Kenneth R. Chien, Kirk U. Knowlton
Published February 15, 2003
Citation Information: J Clin Invest. 2003;111(4):469-478. https://doi.org/10.1172/JCI16491.
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Article Cardiology

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

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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Figure 6

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AAV-directed expression of dnSOCS1 inhibits the CVB3-mediated cytopathic...
AAV-directed expression of dnSOCS1 inhibits the CVB3-mediated cytopathic effect. Hearts of mice were directly injected with AAV Myc-tagged dnSOCS1 or AAV LacZ. Two weeks later, the mice were infected with CVB3. Five days after infection, myocardial sections were stained with anti-Myc (a) or anti–β-galactosidase antibodies (d). Evans blue uptake was examined in the same section (b and e). The merged images (c and f) show that in the areas where there is expression of dnSOCS1, there is a lack of membrane disruption due to the virus infection, as compared with areas of the myocardium that express LacZ. The percent area of Evans blue dye staining in the regions of the myocardium that stained positive for dnSOCS1 or LacZ was quantitated from three mice per group (g) and was significantly decreased in dnSOCS1-expressing areas as compared with LacZ-expressing areas. Results are shown as means ± SE. *P < 0.01 for the comparison with LacZ-transduced areas. Scale bars: 1 mm (a–f).