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.
View: Text | PDF
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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Increased myocardial injury, virus replication, and mortality in SOCS1 t...
Increased myocardial injury, virus replication, and mortality in SOCS1 transgenic mice. (a) Expression of Myc-tagged SOCS1 in the heart was compared among four SOCS1 transgenic lines (A–D) by immunoblotting with anti-Myc antibody (upper panel). Heart tissue extracts for protein (lower left panel) and RNA (lower right panel) from two lines of wild-type and two lines of transgenic mice (A and B) were prepared three days after CVB3 inoculation and probed as shown. (b) Wild-type and SOCS1 transgenic mice (4-week-old males) were inoculated with 103 PFUs of virus (n = 15). The survival rate in infected, SOCS1 transgenic mice was significantly lower than in infected, wild-type littermates (P < 0.0001). (c) Evans blue dye uptake in the heart was markedly increased in surviving SOCS1 transgenic mice on day 4 after infection (red stain, left panels). The percent area of Evans blue staining in the hearts is shown (right panel; mean ± SE, n = 3, *P < 0.01). (d) Increased viral titer in the heart but not the liver of SOCS1 transgenic mice. Virus titers in SOCS1 transgenic and wild-type hearts and livers from 3–5 days after infection (mean ± SE, n = 3, *P < 0.01 comparing SOCS1 transgenic mice with wild-type littermates). (e) Hematoxylin and eosin stains of representative wild-type and SOCS1 transgenic mouse hearts 4 days after infection. Note the thrombus in the center of the ventricle (right panel). Scale bars: 1 mm (c); 100 μm (e, middle); 200 μm (e, right). Tg, transgenic; P-STAT1, phospho-STAT1; P-STAT3, phospho-STAT3.