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

Nature Communications
Naoto MuraokaMasaki Ieda

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.

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Citations

Jan 10, 2020·The Keio Journal of Medicine·Taketaro Sadahiro, Masaki Ieda
Feb 23, 2020·International Journal of Molecular Sciences·Ruizhu Lin, Risto Kerkelä
Oct 22, 2020·International Journal of Molecular Sciences·Lin JiangYigang Wang
Oct 30, 2020·International Journal of Molecular Sciences·Leyre López-MunetaXonia Carvajal-Vergara
Feb 16, 2021·Frontiers in Bioengineering and Biotechnology·Andrew S Riching, Kunhua Song
Feb 9, 2021·Frontiers in Physiology·Francisco SantosBruno Bernardes de Jesus
Aug 25, 2020·Biochimie·Nathalie PizzinatVerena Poinsot
Apr 13, 2021·Frontiers in Bioengineering and Biotechnology·Wangping ChenJianyi Zhang
May 28, 2021·Frontiers in Immunology·Rachael Y M RyanJohn J Miles
Jun 5, 2021·Seminars in Cell & Developmental Biology·Ben Van HandelReza Ardehali
Jul 3, 2021·Seminars in Cell & Developmental Biology·Taketaro Sadahiro, Masaki Ieda
Jul 2, 2021·Inflammation and Regeneration·Hiroyuki Yamakawa, Masaki Ieda
Jul 27, 2021·Frontiers in Physiology·Gustavo Jose Justo da SilvaAlessandro Cataliotti
Jul 12, 2021·Seminars in Cell & Developmental Biology·Glynnis A GarryEric N Olson
Sep 21, 2021·Journal of Biochemical and Molecular Toxicology·Natália H FerreiraDenise C Tavares
Nov 26, 2021·Biochemical Pharmacology·Timothy D Bryson, Pamela Harding

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Methods Mentioned

BETA
fluorescence-activated cell sorting
FACS
electrophoresis
PCR
transfection
ELISA

Software Mentioned

IN Cell
IN Cell Analyzer 6000
Affymetrix Expression Console
GeneSpring GX ( Agilent )

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