Back to Search
Start Over
Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming.
- Source :
-
Nature communications [Nat Commun] 2019 Feb 20; Vol. 10 (1), pp. 674. Date of Electronic Publication: 2019 Feb 20. - Publication Year :
- 2019
-
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.
- Subjects :
- Animals
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Basic Helix-Loop-Helix Transcription Factors metabolism
Cell Differentiation drug effects
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases metabolism
Cyclooxygenase 2 drug effects
Diclofenac pharmacology
Dinoprostone
Fibroblasts
GATA4 Transcription Factor metabolism
Humans
Inflammation
Interleukin-1beta
MEF2 Transcription Factors metabolism
Mice
Mice, Transgenic
T-Box Domain Proteins metabolism
Cellular Reprogramming drug effects
Cyclooxygenase 2 pharmacology
Myocytes, Cardiac drug effects
Receptors, Prostaglandin E, EP4 Subtype drug effects
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30787297
- Full Text :
- https://doi.org/10.1038/s41467-019-08626-y