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The regulation and function of the Hippo pathway in heart regeneration

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Heart failure caused by cardiomyocyte loss and fibrosis is a leading cause of death worldwide. Although current treatments for heart failure such as heart transplantation and left ventricular assist device implantation have obvious value, new approaches are needed. Endogenous adult cardiomyocyte renewal is measurable but inefficient and inadequate in response to extensive acute heart damage. Stimulating self‐renewal of endogenous cardiomyocytes holds great promise for heart repair. Uncovering the genetic mechanisms underlying cardiomyocyte renewal is a critical step in developing new approaches to repairing the heart. Recent studies have revealed that the inhibition of the Hippo pathway is sufficient to promote the proliferation of endogenous cardiomyocytes, indicating that the manipulation of the Hippo pathway in the heart may be a promising treatment for heart failure in the future. We summarize recent findings that have shed light on the function of the Hippo pathway in heart regeneration. We also discuss the mechanisms by which Hippo pathway inhibition promotes heart regeneration and how the Hippo pathway responds to different types of injury or stress during the regenerative process. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration
Overview of the Hippo pathway. The Hippo pathway is composed of several core components: MST1/2, SALV, LATS1/2, and MOB1. Kinases MST1/2 interact with their adaptor SALV and phosphorylate and activate kinases LATS1/2. By interacting with their adaptor MOB1, LATS1/2 interact with and phosphorylate YAP and its analog TAZ. Phosphorylated YAP/TAZ are bound and sequestered by 14‐3‐3 in the cytoplasm or undergo ubiquitination and degradation. When the Hippo pathway is inactivated, unphosphorylated YAP/TAZ translocate into the nucleus, where they interact with their binding partners such as TEA domain family members (TEADs) and regulate the expression of downstream targets
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The regulation of the Hippo pathway in heart regeneration. During heart regeneration, the Hippo pathway responds to different stresses including reactive oxygen species (ROS) and mechanical stress. After injury, the ROS level is increased, which activates NF2 and MST1. RASSF1A plays an essential role in the regulation of apoptosis through the activation of MST1. Matured cardiomyocytes form an intercalated disc (ICD) in the cell‐to‐cell junction, and α‐catenin is a component of ICDs. α‐Catenin interacts with actin and inhibits F‐actin polymerization through the inhibition of Rho kinase. F‐actin polymerization is essential for cell contractility, which regulates YAP activity through an unknown Hippo‐independent mechanism. FAT4 is also a junction protein that interacts and forms a complex with AMOTL1 to sequester YAP on the membrane. A recent study revealed that the extracellular matrix (ECM) regulates YAP activity. AGRIN is a component of the ECM that is enriched in the neonatal heart, and it physically interacts with the dystrophin‐glycoprotein complex (DGC) (Dag is a protein of DGC) and sequesters and inhibits the nuclear translocation of YAP. The dashed line indicates an unknown mechanism
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The role of the Hippo pathway in heart regeneration. The function of the Hippo pathway in cardiomyocytes is the most well studied. The Hippo pathway regulates cardiomyocyte proliferation, cytoskeleton rearrangement, mitochondrial biogenesis, apoptosis, and oxidative stress. YAP activation in cardiomyocytes also inhibits fibrosis and promotes vascularity through cell‐to‐cell communication. In fibroblasts, the Hippo pathway may regulate proliferation, apoptosis, and inflammation. In epicardial cells, the Hippo pathway regulates inflammatory cytokines such as the secretion of interferon γ (IFNγ), which in turn recruits T‐regulatory (Treg) cells and inhibits inflammation and fibrosis. The dashed line indicates an unknown mechanism
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The Hippo pathway in heart development and homeostasis. During the embryonic stage, Hippo activity is low, and YAP activity is high, which is essential for cardiomyocyte proliferation and heart development. Hippo inactivation or YAP activation results in cardiomegaly with excess cardiomyocytes. In the adult stage, Hippo activity is high, and YAP activity is low, causing the heart to lose its regenerative ability. When Hippo is inactivated or YAP is activated, the proliferation of cardiomyocytes is increased, whereas apoptosis is decreased. YAP activation also induces fetal gene expression and cardiomyocytes to undergo dedifferentiation
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