The fibrogenic role of Hippo-Yap signaling following ischemic injury

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PROJECT SUMMARY/ABSTRACT End stage heart failure is a common outcome of cardiac injury such as myocardial infarction (MI). Following ischemic injury, prolonged myofibroblast activation can lead to exacerbated extracellular matrix production, decreased cardiac compliance, myocyte uncoupling, and progressive heart failure. However, an emerging role for myofibroblasts regarding cardiac regenerative healing has been underappreciated and underexplored. Thus, there is great interest in assessing myofibroblast's role in the adult heart following ischemic injury and molecular pathways that can be targeted to control myofibroblast activation and inactivation. In recently published studies we found that genetic deletion of Yap in the regenerative zebrafish model exacerbated scar formation, modulated immune cell infiltration, and delayed cardiac regeneration following cardiac cryoinjury. Yap is a transcriptional activator that promotes cell survival and proliferation that is inhibited by the Hippo signaling pathway through Lats mediated phosphorylation. It was recently reported that either forced expression of Yap, or the deletion of core Hippo kinases extend the regenerative window of cardiomyocytes in neonatal rodent hearts, thus, therapeutically targeting the Hippo-Yap pathway is a promising approach for remuscularization of the heart. However, understanding the role of Yap activity in non-myocytes during cardiac regeneration is critical prior to implementing therapeutic regenerative approaches targeting this pathway. Here, our preliminary data show that Yap is essential for scar formation and resolution in the regenerating zebrafish heart and depletion of Yap in mammalian cardiac fibroblasts modulates fibrotic and inflammatory cyto/chemokine gene programs. Our central theory is that precisely modulating the myofibroblast response by targeting the Hippo-Yap pathway will facilitate critical wound healing and pro-regenerative responses while preventing excessive ECM production and fibrosis in the heart following ischemic injury. Thus, this proposal aims to define the role of Hippo-Yap signaling in myofibroblasts following cardiac injury in adult mice.