# REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $515,761

## Abstract

The Hippo pathway is an evolutionarily conserved signaling mechanism that controls organ size by regulating
cellular growth and death. The Hippo pathway exists in the heart and controls apoptosis, autophagy,
hypertrophy, and proliferation in cardiomyocytes (CMs). YAP is a transcription co-factor and one of the most
prominent terminal effectors of the Hippo pathway. Core kinases in the Hippo pathway, including Mst1 and
Lats2, assemble with the help of hWW45, a scaffolding protein, and their activation induces nuclear exit and
degradation of YAP, thereby negatively regulating YAP function. YAP controls both proliferation and
hypertrophy of CMs and apoptosis in adult CMs, and plays an essential role in maintaining cardiac function
and promoting regeneration in the heart subjected to chronic myocardial infarction (MI). Despite the generally
detrimental effects of the Hippo pathway and the salutary role of YAP in the heart under stress, cardiac-specific
Mst1 and Mst2 double knockout (KO) (Mst1/2cKO) mice and cardiac-specific hWW45 KO (hWW45cKO) mice
develop more severe heart failure (HF) than control hearts in response to pressure overload (PO). These mice
exhibit de-differentiation and decreased contraction of individual CMs. A fundamental question is why CMs
possess the Hippo signaling pathway, if the sole function of the Hippo pathway is to induce cell death. We
hypothesize that: Physiological activation of the Hippo pathway plays an essential role in maintaining
CM function during PO by inhibiting unopposed activation of TEAD through YAP, at the expense of CM
survival. To test this hypothesis, we will first demonstrate the physiological role of the upstream
canonical Hippo pathway in the heart during PO and the role of YAP in mediating the detrimental effect
of Hippo pathway downregulation. We will use Mst1/2cKO and hWW45cKO mice to demonstrate that the
absence of the nuclear Hippo pathway and persistent activation of YAP are detrimental during PO. We will
show that the detrimental effect of Mst1/2cKO and hWW45cKO is mediated through activation of YAP, using
cardiac-specific heterozygous YAP KO (YAPhcKO) mice. We will then show that unopposed activation of
YAP induces de-differentiation of CMs through TEAD1- mediated activation of fetal-type contractile
proteins in the presence of PO. We will cross YAP gain-of-function mouse models, including hWW45cKO and
YAP transgenic mice, with TEAD1+/- mice and show that persistent activation of YAP in CMs induces de-
differentiation of CMs through activation of TEAD1 in the presence of PO. Suppression of the Hippo pathway
and activation of YAP have been considered for treatment of HF, whereas the physiological function of the
Hippo pathway has never been considered previously. We here propose the novel concept that the heart
carries this cell death pathway in order to maintain the differentiation status of CMs. Furthermore, our study will
shed light on a group of cardiomyopathies caused by persistent activati...

## Key facts

- **NIH application ID:** 9849785
- **Project number:** 5R01HL112330-10
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Junichi Sadoshima
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $515,761
- **Award type:** 5
- **Project period:** 2012-02-15 → 2021-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849785

## Citation

> US National Institutes of Health, RePORTER application 9849785, REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY (5R01HL112330-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9849785. Licensed CC0.

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