TY - JOUR
T1 - Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming
AU - Muraoka, Naoto
AU - Nara, Kaori
AU - Tamura, Fumiya
AU - Kojima, Hidenori
AU - Yamakawa, Hiroyuki
AU - Sadahiro, Taketaro
AU - Miyamoto, Kazutaka
AU - Isomi, Mari
AU - Haginiwa, Sho
AU - Tani, Hidenori
AU - Kurotsu, Shota
AU - Osakabe, Rina
AU - Torii, Satoru
AU - Shimizu, Shigeomi
AU - Okano, Hideyuki
AU - Sugimoto, Yukihiko
AU - Fukuda, Keiichi
AU - Ieda, Masaki
N1 - Funding Information:
We thank Ono Pharmaceutical Co., Ltd. for providing the specific antagonists for EP1 (ONO-8713), EP3 (ONO-AE5-599), and EP4 (ONO-AE3-208), and the EP4-specific agonist (ONO-AE1-329). M.I. was supported by research grants from the Research Center Network for Realization of Regenerative Medicine, Japan Agency for Medical Research and Development (AMED), the Japan Society for the Promotion of Science (JSPS) (17K19678, 15K15313), Senshin Medical Research Foundation, Takeda Science Foundation, and Daiichi-Sankyo Foundation of Life Science. N.M. was supported by research grants from the JSPS(15J07407), Keio University Grant-in-Aid for Encouragement of Young Medical Scientists, the Senshin Medical Research Foundation, the Japan Foundation for Applied Enzymology, and the Basic Research of the Japanese Circulation Society.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-08626-y
DO - 10.1038/s41467-019-08626-y
M3 - Article
C2 - 30787297
AN - SCOPUS:85061770613
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 674
ER -