Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming

Naoto Muraoka, Kaori Nara, Fumiya Tamura, Hidenori Kojima, Hiroyuki Yamakawa, Taketaro Sadahiro, Kazutaka Miyamoto, Mari Isomi, Sho Haginiwa, Hidenori Tani, Shota Kurotsu, Rina Osakabe, Satoru Torii, Shigeomi Shimizu, Hideyuki Okano, Yukihiko Sugimoto, Keiichi Fukuda, Masaki Ieda

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. However, postnatal and adult fibroblasts are less efficient for reprogramming compared with embryonic fibroblasts, and barriers to cardiac reprogramming associated with aging remain undetermined. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs. Thus, anti-inflammation represents a new target for cardiac reprogramming associated with aging.

Original languageEnglish
Article number674
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Muraoka, N., Nara, K., Tamura, F., Kojima, H., Yamakawa, H., Sadahiro, T., Miyamoto, K., Isomi, M., Haginiwa, S., Tani, H., Kurotsu, S., Osakabe, R., Torii, S., Shimizu, S., Okano, H., Sugimoto, Y., Fukuda, K., & Ieda, M. (2019). Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming. Nature communications, 10(1), [674]. https://doi.org/10.1038/s41467-019-08626-y