The Hippo Signaling Pathway in Cardiac Development and Diseases

Abstract

Heart disease continues to be the leading cause of morbidity and mortality worldwide. Cardiac malformation during development could lead to embryonic or postnatal death. However, matured heart tissue has a very limited regenerative capacity. Thus, loss of cardiomyocytes from injury or diseases in adults could lead to heart failure. The Hippo signaling pathway is a newly identified signaling cascade that modulates regenerative response by regulating cardiomyocyte proliferation in the embryonic heart, as well as in postnatal hearts after injury. In this review, we summarize recent findings highlighting the function and regulation of the Hippo signaling pathway in cardiac development and diseases.

Keywords: cardiac development; cardiomyoapthies; hippo signaling; hypertrophy; ischemia – reperfusion.

FIGURE 1

Schematic representation of the core components of the Hippo signaling pathway. Several physiological and pathological signals can activate the Hippo signaling pathway in the heart. The physiological signal includes cell–cell interaction, cytokines, and growth factors, whereas the pathological signal includes oxidative stress (ischemia-reperfusion injury), mechanical stress (pressure overload) and injury (myocardial infarction). The core Hippo signaling pathway consists of serine/threonine kinases, transcriptional coactivators, and transcription factors. Upon activation, the upstream kinases (Mst1/2, Lats1/2, Sav1, and MOB1) promote phosphorylation of downstream mediators Yap and Taz, resulting in their cytoplasmic retention or degradation. In contrast, inactivation of upstream kinases leads to nuclear translocation of Yap and Taz, where they bind to various transcription factors including Tead factors (Tead1-4) and regulate target gene expression.

FIGURE 2

An overview of mouse heart development. Heart development begins with the specification of cardiogenic mesoderm cells in the primitive streak at E6.5. At E7.5, these mesodermal precursors migrate away from the primitive streak to form a bow-shaped structure called the cardiac crescent. Cardiac crescent can be divided into two major cardiac progenitor pools: the first and second heart field. The cardiac progenitor cells from the first heart field contribute to the linear heart tube, whereas the second heart field contribute to portions of the atria, the outflow tract, and the right ventricle. As embryonic development proceeds, the progenitor cells fuse at midline and form a primitive linear heart tube. At E8.5, the linear heart tube undergoes looping leading to formation of the outflow tract, primitive ventricles, and atria. At early stages, the heart consists of two layers: an inner endocardium and an outer myocardium. Between E9 and10.5, progenitor cells from different sources (including neural crest and proepicardial organ) migrate and contribute to the outflow tract and ventricular chambers. Myocardial layer expands and forms compact and trabecular myocardium. The proepicardial progenitor cells migrate over the heart surface and form epicardium. Epicardial-derived cells contribute to the formation of the coronary vasculature. Heart maturation involves a series of septation events and valve formation that results in a fully functional four-chambered heart integrated with the circulatory system by E15.5.

FIGURE 3

The role of Hippo signaling components in cardiac development, regeneration/repair, and diseases. (A) During cardiac development, activation/inactivation of the Hippo signaling components modulates proliferation and differentiation of cardiomyocytes, epicardial and endocardial cells, resulting in defective cardiogenesis and embryonic lethality as shown in the figure. (B) Activation/inactivation of the Hippo signaling components differently regulates the regenerative response of neonatal and adult hearts after injury. (C) Activation/inactivation of the Hippo signaling components leads to many cardiac diseases as described in the figure. EPDCs, epicardium-derived cells; EMT, endothelial mesenchymal transition; MI, myocardial infarction; IRI, ischemia/reperfusion injury, TAC, transverse aortic constriction; DMD, Duchenne Muscular Dystrophy.