Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury

Hara, Hironori; Takeda, Norifumi; Kondo, Masaki; Kubota, Mio; Saito, Tatsuo; Maruyama, Junichi; Fujiwara, Takayuki; Maemura, Sonoko; Ito, Masamichi; Naito, Atsuhiko T.; Harada, Mutsuo; Toko, Haruhiro; Nomura, Seitaro; Kumagai, Hidetoshi; Ikeda, Yuichi; Ueno, Hikaru; Takimoto, Eiki; Akazawa, Hiroshi; Morita, Hiroyuki; Aburatani, Hiroyuki; Hata, Yoshinobu; Uchiyama, Masanobu; Komuro, Issei

doi:10.1016/j.jacbts.2018.07.005

Cited by 45 publications

(44 citation statements)

References 28 publications

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“…The precise mechanisms by which TT-10 promoted the hiPSCM proliferation were not analyzed in the present study. In a previous study [4], we revealed that TT-10 not only activated the YAP-TEAD axis, but also had crosstalk with Wnt signaling via mild inhibition of GSK3β. Furthermore, TT-10 upregulated nuclear factor erythroid 2-related factor 2 (NRF-2) and enhanced antioxidant responses in vitro.…”

Section: Discussionmentioning

confidence: 80%

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Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes

Ito

Hara

Takeda

et al. 2019

Journal of Molecular and Cellular Cardiology

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Background: Since regenerative capacity of adult mammalian myocardium is limited, activation of the endogenous proliferative capacity of existing cardiomyocytes is a potential therapeutic strategy for treating heart diseases accompanied by cardiomyocyte loss. Recently, we performed a compound screening and developed a new drug named TT-10 (C 11 H 10 FN 3 OS 2) which promotes the proliferation of murine cardiomyocytes via enhancement of YES-associated protein (YAP)-transcriptional enhancer factor domain (TEAD) activity and improves cardiac function after myocardial infarction in adult mice. Methods and results: To test whether TT-10 can also promote the proliferative capacity of human cardiomyocytes, we investigated the efficacy of TT-10 on human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSCMs). The hiPSCs were established from monocytes obtained from healthy donors and cardiac differentiation was performed using a chemically defined protocol. As was observed in murine cardiomyocytes, TT-10 markedly promoted cell cycle activation and increased cell division of hiPSCMs. We then evaluated other effects of TT-10 on the functional properties of hiPSCMs by gene expression and cell motion analyses. We observed that TT-10 had no unfavorable effects on the expression of functional and structural genes or the contractile properties of hiPSCMs. Conclusions: Our results suggest that the novel drug TT-10 effectively activated the cell cycle of hiPSCMs without apparent functional impairment of myocardium, suggesting the potential of clinical usefulness of this drug.

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Section: Discussionmentioning

confidence: 80%

“…We identified a small molecule, TAZ-12, developed its fluorine substituent TT-10 ( Fig. 1A) and found that TT-10 strongly promoted the proliferation of rat neonatal CMs and activated CM cell division and that it could also potently activate CM cell division in murine hearts after MI [4].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes

Ito

Hara

Takeda

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…It is clear that Mst1/2 inhibition and YAP induction induces cell proliferation in vitro and in vivo. Previous studies using XMU‐MP‐1 (Fan et al, ) and the YAP activator TT‐10 (Hara et al, ) showed increases in proliferation of hepatocytes, small intestinal epithelial cells, and cardiomyocytes following in vivo treatment with the compounds. It is understandable that these data may raise some concerns with regard to the possible development of tumours or cancers, following prolonged use of these compounds.…”

Section: Discussionmentioning

confidence: 93%

“…More recently, a compound, TT‐10 has been described that can induce YAP activity by directly enhancing the transcriptional activity of the YAP–TEAD complex, although the exact molecular mechanism is not completely described. This compound was able to induce cardiomyocyte proliferation both in vitro and in vivo, and treatment with TT‐10, albeit at very high dose, improved the cardiac phenotype in a mouse model of myocardial infarction (Hara et al, ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload

Triastuti

Nugroho

et al. 2019

British J Pharmacology

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Background and PurposeThe Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste‐20 like kinase 1 (Mst1) and mammalian Ste‐20 like kinase 2 (Mst2), modulate cardiac hypertrophy, apoptosis, and fibrosis. Here, we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU‐MP‐1 in controlling the adverse effects of pressure overload‐induced hypertrophy.Experimental ApproachWe used cultured neonatal rat cardiomyocytes (NRCM) and C57Bl/6 mice with transverse aortic constriction (TAC) as in vitro and in vivo models, respectively, to test the effects of XMU‐MP‐1 treatment. We used luciferase reporter assays, western blots and immunofluorescence assays in vitro, with echocardiography, qRT‐PCR and immunohistochemical methods in vivo.Key ResultsXMU‐MP‐1 treatment significantly increased activity of the Hippo pathway effector yes‐associated protein and inhibited phenylephrine‐induced hypertrophy in NRCM. XMU‐MP‐1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. In vivo, mice 3 weeks after TAC, were treated with XMU‐MP‐1 (1 mg·kg−1) every alternate day for 10 further days. XMU‐MP‐1‐treated mice showed better cardiac contractility than vehicle‐treated mice. Cardiomyocyte cross‐sectional size and expression of the hypertrophic marker, brain natriuretic peptide, were reduced in XMU‐MP‐1‐treated mice. Improved heart function in XMU‐MP‐1‐treated mice with TAC, was accompanied by fewer TUNEL positive cardiomyocytes and lower levels of fibrosis, suggesting inhibition of cardiomyocyte apoptosis and decreased fibrosis.Conclusions and ImplicationsThe Hippo pathway inhibitor, XMU‐MP‐1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload.

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“…Recently, a novel drug named TT-10 was described that enhances YAP-TAZ activity, resulting in increased proliferation of murine CMs in vitro (Ito et al, 2019). Intraperitoneal injection of TT-10 in infarcted mice reduced infarct size, improved cardiac function, and increased the numbers of phosphorylated histone-3and Aurora B-positive CMs in the border zone (Hara et al, 2018). These results provide a perspective for pharmacological rather than genetic intervention in Hippo signaling to stimulate CM proliferation in injured hearts.…”

Section: Wnt Signalingmentioning

confidence: 84%

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

Blankesteijn

2019

Mol Pharmacol

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Myocardial infarction is a frequent cardiovascular event and a major cause for cardiomyocyte loss. In adult mammals, cardiomyocytes are traditionally considered to be terminally differentiated cells, unable to proliferate. Therefore, the woundhealing response in the infarct area typically yields scar tissue rather than newly formed cardiomyocytes. In the last decade, several lines of evidence have challenged the lack of proliferative capacity of the differentiated cardiomyocyte: studies in zebrafish and neonatal mammals have convincingly demonstrated the regenerative capacity of cardiomyocytes. Moreover, multiple signaling pathways have been identified in these models that-when activated in adult mammalian cardiomyocytes-can reactivate the cell cycle in these cells. However, cardiomyocytes frequently exit the cell cycle before symmetric division into daughter cells, leading to polyploidy and multinucleation. Now that there is more insight into the reactivation of the cell cycle machinery, other prerequisites for successful symmetric division of cardiomyocytes, such as the control of sarcomere disassembly to allow cytokinesis, require more investigation. This review aims to discuss the signaling pathways involved in cardiomyocyte proliferation, with a specific focus on wingless/int-1 protein signaling. Comparing the conflicting results from in vitro and in vivo studies on this pathway illustrates that the interaction with other cells and structures around the infarct is likely to be essential to determine the outcome of these interventions. The extensive crosstalk with other pathways implicated in cardiomyocyte proliferation calls for the identification of nodal points in the cell signaling before cardiomyocyte proliferation can be moved forward toward clinical application as a cure of cardiac disease. SIGNIFICANCE STATEMENT Evidence is mounting that proliferation of pre-existing cardiomyocytes can be stimulated to repair injury of the heart. In this review article, an overview is provided of the different signaling pathways implicated in cardiomyocyte proliferation with emphasis on wingless/int-1 protein signaling, crosstalk between the pathways, and controversial results obtained in vitro and in vivo.

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Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury

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Cited by 45 publications

References 28 publications

Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes

Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes

Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

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