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 1

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Correlation of CVB3-induced cardiac injury and JAK-STAT activation. (a) ...
Correlation of CVB3-induced cardiac injury and JAK-STAT activation. (a) Mice were infected with CVB3. Protein lysate from the heart was blotted at the indicated days after CVB3 inoculation and probed with the antibodies indicated. (b) Northern blot of total RNA from the heart after CVB3 inoculation was probed for IRF1, FcγRI, SOCS1, and SOCS3 expression. 28S and 18S RNA are shown as controls. (c) Virus titer and the disruption of cardiac cell membrane within 5 days after CVB3 inoculation. Four-week-old male Balb/c mice were inoculated with 103 PFUs of CVB3 intraperitoneally and sacrificed at the day indicated. Evans blue dye was injected intraperitoneally 4 hours before the sacrifice (4). The left panel shows the time course of virus titer (solid line) and the percentage of Evans blue dye–positive area in the heart (gray bars). The Evans blue dye–positive areas were quantitated using NIH image software (NIH, Bethesda, Maryland, USA). The right panels show Evans blue dye–negative (Day 0) and positive (Day 3) sections (the brighter red staining areas). The data were collected from three mice for each time point and expressed as means ± SE. (d) Dual immunostaining of the infected heart demonstrates that the cells that are positive for Evans blue dye are also positive for viral capsid proteins. The left panel shows immunofluorescent staining with anti-CVB3 antibody (green), and the center panel shows Evans blue dye (red) uptake in the same field. The right panel is a merged image. Scale bars: 1 mm (c); 50 μm (d). P-STAT1, phospho-STAT1; P-STAT3, phospho-STAT3.