The Hippo Pathway in Heart Development, Regeneration, and Diseases

Abstract

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 due to 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 very 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 (YAP) transcription co-activator, improves cardiac regeneration. Several known upstream signals of the Hippo pathway such as mechanical stress, G-protein-coupled receptor (GPCR) signaling, and oxidative stress, are known to play critical roles in cardiac physiology. In addition, YAP has been shown to regulate cardiomyocyte fate through multiple transcriptional mechanisms. In this review, we summarize and discuss current findings regarding the roles and mechanisms of the Hippo pathway in heart development, injury, and regeneration.

Building and re-building the heart by cardiomyocyte proliferation

“…The upstream regulators of the Hippo pathway in neonatal cardiomyocytes are not well described; however, a recent report has implicated the microRNA cluster miR302-367, which targets several Hippo signaling kinases and promotes cardiomyocyte proliferation in adult hearts when overexpressed (Tian et al, 2015). The activity of a wide range of transcription factors, most notably in the TEAD family, is stimulated by Yap co-activation (Zhao et al, 2008; reviewed by Zhou et al, 2015). In the mouse heart, sequential chromatin immunoprecipitation experiments have revealed that Yap/TEAD complexes associate with nuclear β-catenin at pro-proliferative Wnt target genes such as Sox2 and Snai2 (Heallen et al, 2011).…”

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

“…The Hippo signaling pathway, a highly conserved serine/threonine kinase cascade, has been shown to play a critical role in the heart through the function of 2 core effector proteins, yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1, referred to herein as TAZ) (22,23). The upstream initiating factors that activate the Hippo pathway remain a topic of intense investigation, and recent studies have shown that GPCRs, as well as mechanical stimuli (i.e., cellular stretch), can engage this signaling cascade (24)(25)(26).…”

Hippo Signaling in the Heart – Non-Canonical Pathways Impact Growth, Survival and Function –

“…65 Cardiac fibrosis was also significantly increased in the RASSF1A -/-mice post-TAC; however, cardiac function was indistinguishdevelopment, growth, survival, proliferation and regeneration in response to injury. 42-48 (For excellent recent reviews please see Zhou et al 49 and Wackerhage et al 50 ) The remaining focus here will be on YAP-independent (ie, non-canonical) cardiac Hippo signaling that lies downstream of 2 integral pathway components, RASSF1A and Mst1.…”