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

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

doi:10.1016/j.jacbts.2018.07.005

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

JACC Basic Transl Sci. 2018 Nov 12;3(5):639-653. doi: 10.1016/j.jacbts.2018.07.005. eCollection 2018 Oct.

Authors

Hironori Hara¹, Norifumi Takeda¹, Masaki Kondo², Mio Kubota², Tatsuo Saito², Junichi Maruyama³, Takayuki Fujiwara¹, Sonoko Maemura¹, Masamichi Ito¹, Atsuhiko T Naito¹, Mutsuo Harada¹, Haruhiro Toko¹, Seitaro Nomura^{1

4}, Hidetoshi Kumagai¹, Yuichi Ikeda¹, Hiroo Ueno⁵, Eiki Takimoto¹, Hiroshi Akazawa¹, Hiroyuki Morita¹, Hiroyuki Aburatani⁴, Yutaka Hata³, Masanobu Uchiyama^{2

6}, Issei Komuro¹

Affiliations

¹ Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.
² Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
³ Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
⁵ Department of Stem Cell Pathology, Kansai Medical University, Osaka, Japan.
⁶ Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry Laboratory, RIKEN, Saitama, Japan.

Abstract

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (C₁₁H₁₀FN₃OS₂) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.

Keywords: BIO, (2ʹZ,3ʹE)-6-bromoindirubin-3ʹ-oxime; EdU, 5-ethynyl-2ʹ-deoxyuridine; FGF1, acidic fibroblast growth factor; Hippo pathway; MI, myocardial infarction; NRF2, nuclear factor erythroid 2-related factor 2; NRG1, neuregulin-1; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, transcriptional enhancer factor domain; Wnt/β-catenin signaling; YAP, YES-associated protein; antioxidation; myocardial infarction; regeneration.