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 and Masaki Ieda ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08626-y

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