Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway

doi:10.7150/ijbs.16430

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Title:	Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway
Authors:	Wu, Jiunn-Ren Yeh, Jwu-Lai Liou, Shu-Fen Dai, Zen-Kong Wu, Bin-Nan Hsu, Jong-Hau
Contributors:	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
Keywords:	Ductus arteriosus Notch signaling remodeling hypertension
Date:	2016
Issue Date:	2018-01-18 11:39:21 (UTC+8)
Publisher:	Ivyspring Int Publ
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 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.
Relation:	International Journal of Biological Sciences, v.12 n.9, pp.1063-1073
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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