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| 標題: | Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway |
| 作者: | Wu, Jiunn-Ren
Yeh, Jwu-Lai
Liou, Shu-Fen
Dai, Zen-Kong
Wu, Bin-Nan
Hsu, Jong-Hau |
| 貢獻者: | Kaohsiung Med Univ, Coll Med, Grad Inst Med
Kaohsiung Med Univ Hosp, Dept Pediat
Kaohsiung Med Univ, Fac Med, Coll Med, Dept Pediat
Kaohsiung Med Univ, Coll Med, Dept & Grad Inst Pharmacol
Chia Nan Univ Pharm & Sci, Dept Pharm |
| 關鍵字: | Ductus arteriosus
Notch signaling
remodeling
hypertension |
| 日期: | 2016 |
| 上傳時間: | 2018-01-18 11:39:21 (UTC+8) |
| 出版者: | Ivyspring Int Publ |
| 摘要: | 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 gamma-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, Ca2+ 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 G(0)/G(1)-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. |
| 關聯: | International Journal of Biological Sciences, v.12 n.9, pp.1063-1073 |
| 顯示於類別: | [藥學系(所)] 期刊論文
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