| Research Abstract |
Cardiac homeostasis is maintained by various kinds of neurohumoral factors. Among them, IL-6 family cytokines play important roles in cardiac protection. In response to pathological stresses, IL-6 family cytokines, such as leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT1) are secreted from cardiac myocytes These cytokines activates three signaling pathways; PI3 kinase/Akt, ERKs, and STAT1/3. In this study, we focused on STAT3 pathway and investigated on its biological significances in cytoprotection, tissue repair and regeneration.
STAT3-mediated cytoprotection: We generated cardiac specific transgenic mice expressing constitutively-active STAT3 (CASTAT3-TG) and analyzed the effects of the overexpression of CASTAT3 on cardiac protection by exposure to ischemia/reperfusion (I/R) injury. CASTAT3-TG hearts exhibited the resistance to I/R injury with the reduction in reactive oxygen species (ROS) production. We also found that CASTAT3-TG hearts showed the upregulation of metallothi
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onein (MT). By using MT-null mice, we demonstrated that MT-dependent ROS scavenging is a critical event for STAT3-mediated cardioprotection.
Roles of STAT3 in cardiac repair : Wnt family proteins play important roles in tissue organization. In this project, we identified Wnt5a as a downstream target of STAT3. STAT3 activation induced Wnt5a, which promoted the expression of N-cadherin in cardiomyocytes. We also demonstrated that IL-6 family cytokines promoted cell-cell interaction via STAT3/Wnt5a/N-cadherin pathway. Since cell-cell interaction is important in the process of cardiac repair after injury, these findings propose the importance of STAT3-mediated induction of Wnt5a in cardiac repair.
Cardiac regeneration and STAT3: Recently cardiac stem cells have been identified as sources of cardiomyocytes. We examined the biological effects of LIF in cardiac stem cells. The stimulation of cardiac stem cells with LIF resulted in the activation of STAT3 and ERK1/2. LIF induced endothelial differentiation in cardiac stem cells, which was inhibited by the inhibition of STAT3 pathway. These findings suggest that LIF induces vasculogenesis in the tissue resident stem cells through STAT3.
The experimental results, described above, propose that STAT3 is a therapeutic target for the onset of heart failure. In this context, we examined the cardioprotective effects of IL-11, because IL-11, a member of IL-6 family, is clinically available with its safety guaranteed. As a result, we found that IL-11 activates STAT3 in cardiac myocytes and that the intravenous administration, prior to I/R injury, exhibited the reduced myocardial damages. Less
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