Regulation of JAK/STAT signalling by SOCS in the myocardium

This editorial refers to ‘SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway’ by A. Cittadini et al., pp. 381–390, this issue. In the myocardium, cytokines are activated in response to acute and chronic cardiac stresses. Some of them, including the interleukin (IL)-6 family of cytokines, have been implicated in cardioprotection, cardiac hypertrophy, inflammation, and heart failure via activation of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway (Figure 1).1–3 Much effort has been made to explore the physiological/pathophysiological functions and mechanisms of positive regulation of the JAK/STAT signalling pathway in cardiac disease. Recent research has placed increasing emphasis on the termination of the signals by suppressors of cytokine signalling (SOCS) proteins.4 In the current issue of Cardiovascular Research, Cittadini et al.5 describe a possible role of SOCS1 in the transition from hypertrophy to heart failure in a chronic pressure-overload cardiac rat model. These authors report that SOCS1 is up-regulated in the decompensated phase of pressure overload. Interestingly, enhanced SOCS1 expression in cardiomyocytes through adeno-associated gene transfer accelerates the transition from hypertrophy to failure associated with sustained inhibition of the glycoprotein 130 (gp130) pathway. These findings support an involvement of SOCS1 in the pathogenesis of heart failure. Schematic diagram of structure and function of SOCS1 and SOCS3. (A) Domain organization of SOCS1 and SOCS3. All SOCS family proteins contain a central SH2 domain and a carboxyl-terminal conserved SOCS box. Both SOCS1 and SOCS3 also have a unique amino-terminal KIR domain. (B) Negative feedback regulation of the IL-6/gp130/JAK/STAT system by SOCS in the myocardium (red arrow). IL-6 family cytokines induce SOCS1 and SOCS3 through the gp130/JAK/STAT signaling pathway. Other cytokines and growth factors also induce SOCS1 and/or SOCS3 in cardiomyocytes. The induced SOCS1 and SOCS3 suppress the gp130/JAK/STAT signalling through (i) blocking the interaction of STATs with receptors by competition via SH2-domain-mediated binding to JAKs and cytokine receptors, (ii) inhibiting the catalytic activity of JAKs through the KIR, (iii) inducing proteasome-mediated degradation of SOCS-binding partners. The IL-6/gp130/JAK/STAT pathway represents a protective mechanism against pathological stresses by inducing cardioprotective agents including anti-apoptotic genes and ROS scavengers and by up-regulating angiogenic factors. However, the excessive activation of this pathway induces excessive NO production and oxidative stress and contributes to the maladaptive response. COX-2, cyclooxygenase 2; iNOS, inducible nitric oxide synthase; MnSOD, manganese superoxide dismutase; MT, metallothioneins; AGT, angiotensinogen; MMP, matrix metalloproteinase. In response to cardiac stresses, cardiomyocytes produce the IL-6 family of cytokines, which includes IL-6, cardiotrophin 1, and leukaemia inhibitory factor.1,2 Each cytokine binds to its receptor, followed by the activation of the common receptor subunit, gp130, which then initiates the activation of JAKs. The activated JAKs phosphorylate the receptor cytoplasmic domains, which create docking sites for STAT molecules. Once bound to the receptor, the STAT proteins are phosphorylated by JAKs, followed by dimerization and translocation into the nucleus, where they interact with specific DNA sequences and transcription factors to regulate the transcription of the target genes. It is now known that a large number of cytokines, growth factors, and hormonal factors also activate the JAK/STAT pathway. It is widely recognized that the JAK/STAT pathway is implicated in a wide array of pathological states in the heart and contributes to both adaptive and maladaptive responses (Figure 1).1 On one hand, accumulating evidence indicates that excessive stimulation of IL-6 cytokines gp130, and the JAK/STAT pathway promotes cardiac hypertrophy, inflammation, and cardiac dysfunction.2,3 On the other hand, results of the studies involving inhibitors and genetic mouse models overwhelmingly support the cardioprotective activities of this pathway through promoting cardiomyocyte survival and angiogenesis,1,6 as also shown in the study by Cittadini et al.5 The authors report that inhibition of the JAK/STAT pathway by SOCS1 overexpression, in the setting of increased haemodynamic overload, increases cardiomyocyte apoptosis and attenuates myocardial production of angiopoietin 2, and vascular endothelial growth factor A, leading to interstitial fibrosis and vascular rarefaction. Because chronic activation of the JAK/STAT pathway promotes inflammation and may have pathological effects on the heart, negative regulation by the SOCS proteins is therefore crucial for maintaining a well-balanced JAK/STAT signalling.2 SOCS proteins constitute a family of eight-related proteins: CIS (cytokine-inducible SH2-domain containing protein) and SOCS1 to SOCS7, of which SOCS1 and SOCS3 have been characterized most intensively. Each SOCS family member has a central SH2 domain, an amino-terminal domain of variable length and sequence, and a carboxyl-terminal 40-residue SOCS box. The SOCS box interacts with elongin B and elongin C, Cullins and the RING finger-domain-only protein RBX2, forming an E3 ubiquitin ligase complex, which mediates the degradation of bound partners of the SOCS proteins through their SH2 domain.7 In addition, both SOCS1 and SOCS3 can inhibit JAK directly through their kinase inhibitory region (KIR) in the amino-terminal region (Figure 1). The SOCS proteins were identified as target genes of the JAKJ/STAT pathway, forming a negative-feedback loop to inhibit signal propagation.4,8 They can also be induced by other signalling pathways independent of JAK/STAT signalling. The list of inducers of SOCS proteins in the myocardium is growing; included among them are IL-6 cytokines, interferon (INF) γ, tumour necrosis factor (TNF) α, and angiotensin II. In this context, the study by Cittadini et al.5 shows that acute mechanical stretch to the isolated perfused hearts induces SOCS1 up-regulation, which is in part dependent on TNFα activation, and that TNFα up-regulation parallels the increased SOCS1 expression in chronic pressure overload. SOCS proteins are relatively novel physiological regulators of the JAK/STAT signalling pathway and their contributions to cardiac disease are comparatively less explored among the key components in this pathway. Accumulating evidence supports a role for SOCS3 in cardiac hypertrophy and failure. Myocardial SOCS3 expression is up-regulated at the onset of the development of cardiac hypertrophy by pressure overload9 and also by angiotensin II.10 Overexpression of SOCS3 in cultured cardiomyocytes suppresses gp130-mediated myocyte hypertrophy and survival.9 Cardiac-specific overexpression of SOCS3 increases susceptibility to viral infection of the heart due to the blockade of JAK/STAT signalling.11 Cardiac-specific deletion of SOCS3 prevents cardiac remodelling after acute myocardial infarction.12 These in vitro and in vivo studies support a detrimental role of myocardial SOCS3 in cardiac remodelling by blocking the beneficial effects of STAT3 signalling and suggest that SOCS3 inhibition could be beneficial in treating a heart under stress by maintaining the sensitivity of the myocardium to the IL-6 family cytokines. Studies on SOCS1 in the heart support a role for SOCS1 in cardiac inflammation. Overexpression of SOCS1 produces protective (including anti-inflammatory) effects in autoimmune myocarditis13 and sepsis-induced myocardial depression.14 However, similar to SOCS3, cardiac-specific overexpression of SOCS1 increases susceptibility to viral infection of the heart.15 These studies suggest that SOCS1 gene transfer can effectively treat some clinical cases of myocarditis and inflammatory cardiomyopathy associated with autoimmunity. In the context of cardiac remodelling in pathological cardiac hypertrophy, overexpression of SOCS1 in cultured cardiomyocytes suppresses gp130-mediated myocyte hypertrophy and survival, but the in vivo function remains unclear.9 In this regard, the study Cittadini et al.5 provides in vivo evidence for a detrimental role of SOCS1 overexpression in cardiac remodelling by blocking the beneficial effects of STAT3 signalling. Different from SOCS3, SOCS1 expression is up-regulated in the decompensated phase, but not at the onset, of cardiac hypertrophy induced by pressure overload. It should be noted that the endogenous role of SOCS1 in cardiac remodelling remains to be confirmed/determined by a loss-of-function approach. The IL-6 family cytokines, gp130/JAK/STAT signalling, and negative-feedback regulation by SOCS proteins are crucial to the pathophysiology of cardiac hypertrophy and heart failure. The importance of JAK/STAT signalling in mediating both protective and harmful effects on cardiomyocytes is well established. The mechanisms of regulating this pathway have been significantly advanced during the past decade since the discovery of the SOCS protein family. Further research is warranted to investigate the roles of SOCS proteins in cardiac disease and their value as therapeutic targets. Conflict of interest: none declared.