Glycoprotein 130 cytokine signal as a therapeutic target against cardiovascular diseases
Yasushi Fujio1, Makiko Maeda, Tomomi Mohri
1Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Japan. fujio@phs.osaka-u.ac.jp
Insights
Interleukin-6 (IL-6) family cytokines, particularly interleukin-11 (IL-11), protect the heart by activating the JAK/STAT pathway. IL-11 shows promise as a readily available cardioprotective therapy.
Area of Science:
- Cardiovascular Biology
- Immunology
- Regenerative Medicine
Background:
- Postnatal cardiomyocytes exhibit limited proliferation, necessitating intrinsic myocardial protective mechanisms.
- Autocrine/paracrine signaling, including cytokines, plays a crucial role in myocardial protection against stress.
- Interleukin-6 (IL-6) family cytokines, signaling through glycoprotein 130 (gp130), are key players in these protective systems.
Purpose of the Study:
- To review the role of IL-6 family cytokines, specifically gp130 cytokines, in cardioprotection.
- To explore the signaling pathways activated by gp130, including JAK/STAT, ERK, and PI3K/Akt.
- To evaluate the therapeutic potential of interleukin-11 (IL-11) for cardioprotection.
Main Methods:
- Review of existing literature on IL-6 family cytokines and their role in cardiac function.
- Analysis of signaling pathways downstream of gp130 activation in cardiomyocytes and cardiac stem cells.
- Examination of studies investigating IL-11's effects on ischemia/reperfusion injury and cardiac remodeling.
Main Results:
- gp130 signaling in cardiomyocytes promotes survival and angiogenesis via the JAK/STAT pathway.
- Activation of gp130 in cardiac stem cells induces endothelial transdifferentiation, enhancing neovascularization.
- IL-11 demonstrates preconditioning effects in ischemia/reperfusion models and prevents cardiac remodeling post-coronary ligation via JAK/STAT.
Conclusions:
- The JAK/STAT pathway is a critical mediator of gp130-induced cardioprotection and a potential therapeutic target for cardiovascular diseases.
- Interleukin-11 (IL-11) exhibits significant cardioprotective effects, including preconditioning and prevention of adverse remodeling.
- Given its clinical availability for thrombocytopenia, IL-11 is a promising candidate for cardioprotection therapy.
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.
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