Glycoprotein 130 Cytokine Signal as a Therapeutic Target Against Cardiovascular Diseases

Abstract

Abstract. Postnatal cardiomyocytes have only limited capacity of proliferation. Therefore, the myocardium is intrinsically equipped with cardioprotective machineries and protects itself from pathological stresses. One of the most important cardioprotective systems is the signal network of autocrine/paracrine factors, including neurohumoral factors, growth factors, and cytokines. In this review, we focus on the roles of interleukin-6 (IL-6) family cytokines, also known as glycoprotein 130 (gp130) cytokines, in cardioprotection. These cytokines make a complex with their specific cytokine receptor α-subunits. The cytokine-receptor α-subunit complex binds to gp130, a common receptor of the IL-6 family, followed by the activation of JAK/STAT, ERK, and PI3 kinase/Akt pathways. In cardiomyocytes, signals through gp130 promote cell survival and angiogenesis through the JAK/STAT pathway. Activation of gp130 in cardiac stem cells induces their endothelial transdifferentiation, leading to neovascularization. Recently, accumulating evidence has revealed that altered JAK/STAT activity is associated with heart failure, suggesting that the JAK/STAT pathway is a therapeutic target against cardiovascular diseases. Interestingly, activation of the JAK/STAT pathway with interleukin-11 (IL-11) exhibits preconditioning effects in ischemia/reperfusion model. Moreover, IL-11 treatment after coronary ligation prevents cardiac remodeling through the JAK/STAT pathway. Since IL-11 is used for patients with thrombocytopenia, we propose that IL-11 is a candidate cytokine clinically available for cardioprotection therapy.

Interleukin-11 protects against renal ischemia and reperfusion injury

“…Therefore, site-specific PEGylation is an innovative application to increase the potency and half-life of IL-11 (by more than 10-fold to ϳ300 -500 min in rats; unpublished data). After IL-11 binds to the IL-11 receptor, the ligand-receptor complex interacts with a common receptor subunit, glycoprotein 130 (gp130), leading to gp130-associated kinase-mediated tyrosine phosphorylation (11). The cytoprotective mechanisms of IL-11 leading to reductions in necrosis, inflammation, and apoptosis have been investigated in other cell types.…”

“…The cytoprotective mechanisms of IL-11 leading to reductions in necrosis, inflammation, and apoptosis have been investigated in other cell types. In cardiomyocytes, IL-11 reduces injury and fibrosis by JAK-STAT3 (Janus kinase-signal transducer and activator of transducer 3) pathway activation (11,26,40). In vascular endothelial and intestinal epithelial cells, IL-11 protects against oxidant-induced necrosis and apoptosis via mechanisms involving ERK MAPK, Akt (protein kinase B), and/or induction of heat shock protein 25 (39,44,61).…”

Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

“…Therefore, these cardioprotective signaling pathways are believed to be therapeutic targets against cardiovascular diseases (5). However, unexpectedly, recent studies have proposed that signaling molecules may exhibit differential functions depending on their kinetics.…”

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

“…The mechanism underlying this effect may be attributed to the stimulation of STAT3 activated by IL-11. As described previously (13), cardiac myocytes release large quantities of IL-6 family cytokines, including IL-11, in conditions of pathological stress. These cytokines activate a common signaling pathway, the JAK/STAT pathway, through their unique receptor system.…”

“…We therefore suspect that our results were also attributed to a different pathway existing upstream of apoptosis. It has been shown that STAT3 not only influences the apoptotic pathway but also reduces reactive oxygen species (ROS); the JAK/ STAT3 pathway upregulates the transcription of manganese superoxide dismutase and metallothionein, both of which are known ROS scavengers (13). ROS act as mediators for post-ischemic myocardial stunning, and studies have shown that reperfusion of the ischemic hearts with ROS scavengers improves functional recovery and reduces the occurrence of IR-induced arrhythmias (18).…”