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, 116 (8), 1431-47

The Hippo Pathway in Heart Development, Regeneration, and Diseases


The Hippo Pathway in Heart Development, Regeneration, and Diseases

Qi Zhou et al. Circ Res.


The heart is the first organ formed during mammalian development. A properly sized and functional heart is vital throughout the entire lifespan. Loss of cardiomyocytes because of injury or diseases leads to heart failure, which is a major cause of human morbidity and mortality. Unfortunately, regenerative potential of the adult heart is limited. The Hippo pathway is a recently identified signaling cascade that plays an evolutionarily conserved role in organ size control by inhibiting cell proliferation, promoting apoptosis, regulating fates of stem/progenitor cells, and in some circumstances, limiting cell size. Interestingly, research indicates a key role of this pathway in regulation of cardiomyocyte proliferation and heart size. Inactivation of the Hippo pathway or activation of its downstream effector, the Yes-associated protein transcription coactivator, improves cardiac regeneration. Several known upstream signals of the Hippo pathway such as mechanical stress, G-protein-coupled receptor signaling, and oxidative stress are known to play critical roles in cardiac physiology. In addition, Yes-associated protein has been shown to regulate cardiomyocyte fate through multiple transcriptional mechanisms. In this review, we summarize and discuss current findings on the roles and mechanisms of the Hippo pathway in heart development, injury, and regeneration.

Keywords: Yes-associated protein; cardiomegaly; stem cells.


Figure 1
Figure 1. The mammalian Hippo pathway
Arrows or blunt ends indicate activation or inhibition, respectively. Dashed lines indicate unknown mechanisms. Abbreviations: AJ (Adherens Junctions), CK1δ/ε (casein kinase 1 δ/ε), DLG (Disks large homolog), KBR (Kibra), LGL (Lethal giant larvae protein homolog), Scrib (Protein scribble homolog), SCF (Skp, Cullin, F-box containing complex), β-TRCP (β-Transducin repeat-containing protein), SWI/SNF (SWItch/Sucrose NonFermentable nucleosome remodeling complex), TJ (Tight Junctions), Ub (Ubiquitin), ZO-1 (Tight junction protein ZO-1, also called TJP1), α-CAT (α-Catenin).
Figure 2
Figure 2
Transcription effectors of the Hippo pathway in regulation of cardiac physiology. YAP/TAZ transcription factor partners in cardiomyocytes and their downstream target genes are shown. The Hippo pathway likely regulates cardiac physiology through a coordinated transcriptional program. Abbreviations: DVL (Dishevelled), p300 (E1A binding protein p300), pCAF (p300/CBP-associated factor, KAT2B), TCF/LEF (Transcription factor/Lymphoid enhancer-binding factor).

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