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

Author

Listed:
  • Naoto Muraoka

    (Keio University School of Medicine)

  • Kaori Nara

    (Keio University School of Medicine)

  • Fumiya Tamura

    (Keio University School of Medicine)

  • Hidenori Kojima

    (Keio University School of Medicine)

  • Hiroyuki Yamakawa

    (Keio University School of Medicine)

  • Taketaro Sadahiro

    (University of Tsukuba)

  • Kazutaka Miyamoto

    (Keio University School of Medicine)

  • Mari Isomi

    (University of Tsukuba)

  • Sho Haginiwa

    (Keio University School of Medicine)

  • Hidenori Tani

    (Keio University School of Medicine)

  • Shota Kurotsu

    (Keio University School of Medicine)

  • Rina Osakabe

    (Keio University School of Medicine)

  • Satoru Torii

    (Tokyo Medical and Dental University (TMDU))

  • Shigeomi Shimizu

    (Tokyo Medical and Dental University (TMDU))

  • Hideyuki Okano

    (Keio University School of Medicine)

  • Yukihiko Sugimoto

    (Kumamoto University)

  • Keiichi Fukuda

    (Keio University School of Medicine)

  • Masaki Ieda

    (University of Tsukuba)

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.

Suggested Citation

  • Naoto Muraoka & Kaori Nara & Fumiya Tamura & Hidenori Kojima & Hiroyuki Yamakawa & Taketaro Sadahiro & Kazutaka Miyamoto & Mari Isomi & Sho Haginiwa & Hidenori Tani & Shota Kurotsu & Rina Osakabe & Sa, 2019. "Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08626-y
    DOI: 10.1038/s41467-019-08626-y
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    Cited by:

    1. Maria A. Missinato & Sean Murphy & Michaela Lynott & Michael S. Yu & Anaïs Kervadec & Yu-Ling Chang & Suraj Kannan & Mafalda Loreti & Christopher Lee & Prashila Amatya & Hiroshi Tanaka & Chun-Teng Hua, 2023. "Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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