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 activation of YAP and consequent de- differentiation of CMs, as well as the possible treatment of these diseases with YAP inhibitors.

Public Health Relevance

We will investigate why the Hippo signaling pathway, known to promote death of cardiomyocytes, exists in the heart. Our hypothesis is that the activity of the Hippo pathway is required for the heart cells to maintain a well-organized structure and to generate contractile force against blood pressure. Disruption of this mechanism may be responsible for the cardiac dysfunction observed in some forms of cardiomyopathy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Schwartz, Lisa
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Rutgers University
Anatomy/Cell Biology
Schools of Medicine
United States
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Ikeda, Shohei; Mizushima, Wataru; Sciarretta, Sebastiano et al. (2018) Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte De-Differentiation During Pressure Overload. Circ Res :
Sciarretta, Sebastiano; De Falco, Elena; Frati, Giacomo et al. (2017) How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium. Ann Transl Med 5:52
Nagarajan, Narayani; Oka, Shinichi; Sadoshima, Junichi (2017) Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic Biol Med 109:125-131
Sadoshima, Junichi (2017) Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School. Circ Res 121:1127-1129
Sadoshima, Junichi; Tomoike, Hitonobu (2017) What Should We Learn From the Recent Decline of Basic Cardiovascular Science in Japan? Circ Res 121:314-316
Oka, Shin-Ichi; Hirata, Tsuyoshi; Suzuki, Wataru et al. (2017) Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes. J Biol Chem 292:18988-19000
Saito, Toshiro; Sadoshima, Junichi (2017) Unexpected Functional Consequences of the Loss of the Autophagy-Related Conjugation System. Circ Res 120:610-612
Mizushima, Wataru; Sadoshima, Junichi (2017) BAG3 plays a central role in proteostasis in the heart. J Clin Invest 127:2900-2903
Matsuda, Takahisa; Zhai, Peiyong; Sciarretta, Sebastiano et al. (2016) NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart. Circ Res 119:596-606
Matsushima, Shouji; Zablocki, Daniela; Tsutsui, Hiroyuki et al. (2016) Poldip2 negatively regulates matrix synthesis at focal adhesions. J Mol Cell Cardiol 94:10-12

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