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

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

“…Coxsackievirus usually infects cardiomyocytes and induces the expression of SOCS1 and SOCS3 in cardiomyocytes, which can result in evasion of immune responses and facilitation of virus replication by inhibition of JAK-STAT signaling (32,37). These findings indicate that it may be harmful to administer SOCS1 DNA in the acute phase of infectious myocarditis because it may augment viral replication by inhibition of IFN signaling.…”

“…These findings indicate that it may be harmful to administer SOCS1 DNA in the acute phase of infectious myocarditis because it may augment viral replication by inhibition of IFN signaling. The effect of SOCS1 transduction on viral myocarditis has been examined by Yasukawa et al (32). The SOCS1-transgenic mice infected with CVB3 showed increased myocardial injury, virus replication, and mortality.…”

“…SOCS1 DNA administration inhibits the development of myocarditis induced by cardiac myosin peptide-loaded BMDC transfer but not by CD4 + T cell transfer Functionally interposed SOCS1 is induced in various cell populations, including leukocytes, vascular cells, and cardiomyocytes (18,31,32). A mouse model of EAM was established by cell transfer using peptide-pulsed DCs or cardiac epitope-specific CD4 + T cells (7,14).…”

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

“…[21][22][23] The pBSII-aMHC-LOXL-1 vector was constructed by subcloning the human LOXL-1 cDNA (accession no: NM_005576) into the pBSII-aMHC plasmid (generously provided by S Morimoto, Kyushu University). After digestion with SalI, the fragment carrying the aMHC promoter and human LOXL-1 cDNA was microinjected into (C57BL/6 Â C3H) F1 (B6C3-F1) zygotes.…”

“…Mice were anesthetized with isoflurane and subjected to echocardiography as previously described. [22][23][24] Recording was performed as described previously. [22][23][24] …”