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
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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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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Effect of SOCS1 and SOCS3 on the cytoprotective effect of IFNs and CT-1 ...
Effect of SOCS1 and SOCS3 on the cytoprotective effect of IFNs and CT-1 in cultured cardiomyocytes. (a) Myc-tagged SOCS1 or SOCS3 was expressed in neonatal rat cardiomyocytes with the use of recombinant adenovirus vectors (20) (black or gray bars, respectively). The vector containing the LacZ gene was used as a control for adenoviral vector infection (white bars). After transduction with the adenoviral vectors, the cells were stimulated with IFN-γ, IFN-β, or CT-1 for 24 hours. Cells were then infected with CVB3 (+) or maintained without virus (–) for another 30 hours. The number of cells that remained on the plate after CVB3 infection was quantitated and reported as a percentage of cells in the wells not infected with CVB3. The data are from five independent experiments and are expressed as means ± SE. *P < 0.01 for the comparison with cells transduced with adenovirus LacZ, stimulated with cytokines, and infected with CVB3. **P < 0.01 for the comparison with cells transduced with adenovirus LacZ, not stimulated with cytokines, and infected with CVB3. (b) Myocytes were incubated with adenovirus LacZ, adenovirus SOCS1, or adenovirus SOCS3, serum depleted for 24 hours, and then stimulated with 1000 ng/ml IFN-γ for 5 hours or 1 nM CT-1 for 10 minutes. Total cell extracts were prepared and blotted with phospho-STAT1, STAT1, phospho-STAT3, and STAT3 antibodies. SOCS1 and SOCS3 expression were confirmed with an anti-Myc antibody. Representative Western blots from three independent experiments are shown. SOCS1, adenovirus containing Myc-tagged SOCS1 gene; SOCS3, adenovirus containing Myc-tagged SOCS3 gene; LacZ, adenovirus containing LacZ; Stim, stimulated, P-STAT1, phospho-STAT1; P-STAT3, phospho-STAT3.