Activation of JAK-STAT signaling is a common feature of preconditioning and agents that are cardioprotective, including the IL-6-type cytokines. However, mechanisms regulating IL-6 cytokine signaling in the heart are largely unexplored. We propose that the magnitude and protective character of IL-6-type signaling in cardiac muscle is determined by several distinct mechanisms during preconditioning and periods of ischemic stress, including redox-regulation of the JAK kinases and expression of Suppressor of Cytokine Signaling 3 (SOCS3) that terminates IL-6-type cytokine signaling. For the IL-6-family cytokines to be cardioprotective and for preconditioning to occur, we propose that the cellular redox status needs to be maintained and SOCS3 induction in cardiac myocytes must be minimal. Moreover, we hypothesize that while myocardial induction of SOCS3 may prove detrimental to the heart, endothelial SOCS3 is cardioprotective in part by opposing eNOS downregulation. To investigate regulatory mechanisms of cardiac IL-6-family signaling, we propose 3 aims.
Aim 1 is to establish the importance of JAK1 redox-sensitivity for ischemic preconditioning. We will assess the impact of glutathione depletion in vivo on IL-6-family cytokine signaling and preconditioning. Mutagenesis and biochemical experiments will be performed to define the mechanism for JAK1 redox- sensitivity. We will also assess if in vivo delivery of a redox-insensitive JAK1 mutant enhances or restores preconditioning protection.
Aim 2 will establish the role of the STAT3 - SOCS3 axis in cardiac endothelial cell function. Using cultured mouse coronary endothelial cells from mice carrying a STAT3 S727A mutation, we will test the hypothesis that while binding of STAT3 to promoter elements does not require STAT3 Ser727 phosphorylation, STAT3 transcriptional activity does. We will assess the involvement of STAT3 Ser727 phosphorylation in IL-6 cytokine-induced SOCS3 and vascular endothelial growth factor (VEGF) expression, and eNOS downregulation. We will also test the novel hypothesis that SOCS3 physically interacts with eNOS, and thereby leads to its degradation.
Aim 3 is to establish the role of myocardial and endothelial SOCS3 in ischemic preconditioning and will employ a closed-chest mouse myocardial ischemia-reperfusion model. Using cardiomyocyte-targeted SOCS3 knockout mice, we will assess the consequences of myocardial SOCS3 deletion on early and late preconditioning. Mice with targeted loss of SOCS3 in endothelial cells will be used to test the hypothesis that endothelial cell SOCS3 expression is necessary for preconditioning and for preventing endothelial dysfunction. Accomplishment of these aims will vastly extend knowledge of how IL-6 cytokine signaling in the heart is regulated and will have significance for exploiting the therapeutic potential of these cytokines and the phenomenon of preconditioning.
The heart can be protected against damage due to a lack of oxygen by an experimental technique called ischemic preconditioning, which involves briefly shutting off its blood supply. A number of factors are involved in preconditioning, including certain cytokines that activate a particular signaling cascade in heart cells. Our research is focused on understanding how that cascade is turned on and off with the hope that this knowledge could be used therapeutically to prevent ischemic damage to the heart.
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