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Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway
- Source :
- International Journal of Biological Sciences
- Publication Year :
- 2016
-
Abstract
- Patent ductus arteriosus (PDA) can cause morbidity and mortality in neonates. Vascular remodeling, characterized by proliferation and migration of smooth muscle cells (SMCs), is an essential process for postnatal DA closure. Notch signaling is an important mediator of vascular remodelling but its role in DA is unkonwn. We investigated the effects and underlying mechanisms of γ-secretase inhibitor DAPT, a Notch signaling inhibitor on angiotensin II (Ang II)-induced proliferation and migration of DASMCs. Proliferation and migration of DASMCs cultured from neonatal Wistar rats were induced by Ang II, with or without DAPT pre-treatment. In addition, potential underlying mechanisms including cell cycle progression, Ca(2+) influx, reactive oxygen species (ROS) production, signal transduction of MAPK and Akt, and Notch receptor with its target gene pathway were examined. We found that DAPT inhibited Ang II-induced DASMCs proliferation and migration dose dependently. DAPT also arrested the cell cycle progression in the G0/G1-phase, and attenuated calcium overload and ROS production caused by Ang II. Moreover, DAPT inhibited nuclear translocation of Notch3 receptor intracellular domain, with decreased expression of its down-stream genes including HES1, HES2 and HES5. Finally, Ang II-activated ERK1/2, JNK and Akt were also counteracted by DAPT. In conclusion, DAPT inhibits Ang II-induced DASMCs proliferation and migration. These effects are potentially mediated by decreased calcium influx, reduced ROS production, and down-regulation of ERK1/2, JNK and Akt, through the Notch3-HES1/2/5 pathway. Therefore, Notch signaling has a role in DA remodeling and may provide a target pathway for therapeutic intervention of PDA.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
medicine.medical_specialty
Myocytes, Smooth Muscle
HES5
Notch signaling pathway
Biology
Diamines
Applied Microbiology and Biotechnology
03 medical and health sciences
Cell Movement
Pregnancy
Internal medicine
medicine
Basic Helix-Loop-Helix Transcription Factors
Animals
HES1
Rats, Wistar
Receptor
Molecular Biology
Protein kinase B
Receptor, Notch3
Ecology, Evolution, Behavior and Systematics
Cells, Cultured
Notch signaling
Cell Proliferation
remodeling
Receptors, Notch
Angiotensin II
Cell Biology
Ductus Arteriosus
Cell biology
Rats
Repressor Proteins
Thiazoles
030104 developmental biology
Endocrinology
Transcription Factor HES-1
Female
Signal transduction
Reactive Oxygen Species
Developmental Biology
Signal Transduction
Research Paper
Subjects
Details
- ISSN :
- 14492288
- Volume :
- 12
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- International journal of biological sciences
- Accession number :
- edsair.doi.dedup.....68b9865117662cb83861353a3f669327