Alterations in Janus Kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) Signaling in Patients With End-Stage Dilated Cardiomyopathy

Abstract

Background-Experimental studies indicate that interleukin-6 (IL-6)-related cytokines, signaling via the shared receptor gp130, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs), provide a critical cardiomyocyte survival pathway in vivo. Little is known about the activation of this signaling pathway in the myocardia of patients with end-stage dilated cardiomyopathy (DCM). Methods and Results-We performed a comprehensive expression and activation analysis of IL-6 -related cytokines, receptors, signal transducers, and signal transduction inhibitors in left ventricular (LV) myocardia from patients with DCM (nϭ10) and non-failing (NF) donor hearts (nϭ5 Key Words: cardiomyopathy Ⅲ interleukins Ⅲ signal transduction D ilated cardiomyopathy (DCM) represents a common end-stage disease state of the myocardium in response to different environmental and genetic factors, a fact that has led to the proposition of shared signaling pathways for cardiac dilation and failure. 1 In this regard, a growing body of evidence indicates that interleukin-6 (IL-6)-related cytokines signaling via the shared receptor gp130 provide a critical myocyte survival pathway in vivo. Most notably, genetargeted mice with a cardiomyocyte-restricted deletion of gp130 develop massive cardiomyocyte apoptosis and dilated cardiomyopathy when subjected to biomechanical stress. 2 A prevailing concept predicts that an intricate balance between cardiomyocyte hypertrophy and apoptosis determines heart failure progression. 1 In this regard, the Janus kinases-signal transducers and activators of transcription (JAK-STAT) signaling pathway has been shown to mediate hypertrophic and cytoprotective effects of gp130 activation in cardiomyocytes. 2-8 IL-6 -related cytokines potently activate gp130, which in turn promotes tyrosine-phosphorylation (ie, activation) of JAKs and cytoplasmic latent transcription factors of the STAT family. 9 Signaling via gp130 and JAK-STAT is controlled in a negative-feedback fashion by a family of proteins referred to as suppressors of cytokine signaling, including SOCS1 and SOCS3. 10,11 Despite increasing evidence implicating IL-6 -related cytokines, gp130, and JAK-STAT as a critical myocyte survival pathway, little is known regarding expression and activation of this pathway in patients with DCM. In the present study, we have conducted a comprehensive expression and activation analysis of the gp130-JAK-STAT signaling cascade in left ventricular (LV) myocardia from patients with DCM. Methods Patient PopulationLV myocardium was obtained from patients undergoing heart transplantation because of end-stage DCM (nϭ10; mean age: 44Ϯ13 years; New York Heart Association functional classes III and IV; LV ejection fraction: 16Ϯ7%; LV end-diastolic diameter: 65Ϯ14 mm). ImmunohistochemistryImmunohistochemistry was performed on serial sections from NF and DCM hearts using antibodies from New England Biolabs (Beverly, Mass, JAK2), Cell Signaling Technology (STAT3), Biomeda (Foster City, Calif, skeletal muscle ␣-actin...

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

“…Not much information is available to date on the expression state of SOCS proteins, negative regulators of gp130-JAK/STAT signaling, in human failing hearts. One report shows that terminally failing human hearts display increased SOCS-1 and reduced SOCS-3 protein levels [113]. Taken together, circulating IL-6 cytokines positively correlate with the progression of heart failure and the local IL-6-gp130-STAT3 signaling cascade in human failing hearts is dysregulated at all levels.…”

“…■ Changes in myocardial expression of the IL-6 type family of cytokines Intriguingly, not only systemic levels of IL-6 type cytokines and sgp130 are elevated in cardiovascular disease but also the local gp130-STAT3 signaling cascade is altered at every level in the failing human heart [28, 67,68,113,175]. For instance, it is known that both CT-1 and LIF are increasingly expressed in the failing left ventricular myocardium.…”

“…On the other hand myocardial levels of IL-6 and LIF receptor appear to be reduced in patients with dilative cardiomyopathy [28,67]. Interestingly, while the gp130 receptor was found to be hyperphosphorylated [113], gp130 protein expression is not altered [113] or even diminished in the failing left ventricular myocardium [175]. Expression and phosphorylation levels of STAT3 [52,113], the major downstream signaling molecule of IL-6, as well as phosphorylation of its upstream activators JAK2 and TYK1 is severely reduced in failing hearts of different etiology [113].…”

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

“…Although the ligand-binding IL-6R alone is not capable of signal transduction, the signaling component gp130 is also involved in the transduction of signals from other ligands of the IL-6 family. When IL-6 is induced by sustained β-adrenoceptor activation, the capacity for signal transduction by IL-6 is probably maintained, because: (a) we found no lowering in the myocardial mRNA expression of IL-6R or gp130 in any model with sustained β-adrenergic activation; (b) in cardiomyocytes, isoproterenol causes a delayed activation of STAT3 (a hallmark of gp130-dependent signal transduction), which can be attenuated by an IL-6-neutralizing antibody (6); and (c) in failing human myocardium, other studies have demonstrated phosphorylation of gp130 and of downstream signaling components (STAT1, STAT3) (24,25).…”

The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model

“…STAT3 in particular mediates a signal transduction that promotes cellular growth and reverses apoptosis, and thus plays a key role in neovascularization and cellular survival. Studies have shown that deletion of STAT3 in mice causes cardiomyopathy (14), and in patients with the disease, the level of STAT3 in the myocardia was significantly low (15). All these suggest that activating the JAK/STAT3 pathway may be the key to preventing the onset of heart failure.…”