Abstract
Myocardial infarction (MI) is a leading cause of death worldwide. During an MI, the contractile myocardium experiences reduced blood flow causing expansive cell death. Since adult mammalian hearts lack regenerative capacity, MI damage is permanent followed by heart failure. However, recent studies have demonstrated that the neonatal mouse heart exhibits transient regenerative potential within the first 7 days, suggesting a regulatory mechanism that prevents the adult from initiating a regenerative response to cardiac injury. The Hippo signaling pathway negatively regulates mammalian cardiac regeneration by inhibiting the activity of downstream effector YAP. However, YAP5SA, which completely bypasses Hippo pathway regulation, results in YAP hyper-transcriptional activity and heart overgrowth. In this work, we aim to investigate the TEAD-independent mechanisms of YAP in promoting cardiomyocyte (CM) division and renewal. We generated another YAP protein, which can not only skip Hippo pathway inhibition, but also lose the interaction with TEADs. We found that this modified YAP promoted CM proliferation and improved cardiac repair post MI injury. Our work will uncover novel functions of YAP and improve YAP therapeutics in myocardial infarction, finally benefiting human heart health.
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