title: Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway.
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.
authors: 1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 3. Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Jiunn-Ren
authors: JR
authors: Wu
authors: 1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4. Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Jwu-Lai
authors: JL
authors: Yeh
authors: 5. Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
authors: Shu-Fen
authors: SF
authors: Liou
authors: 1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 3. Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Zen-Kong
authors: ZK
authors: Dai
authors: 4. Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Bin-Nan
authors: BN
authors: Wu
authors: 1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 3. Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Jong-Hau
authors: JH
authors: Hsu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003959:Diamines / Q000494:pharmacology*; D004373:Ductus Arteriosus / Q000166:cytology*; D005260:Female; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000804:Angiotensin II; D051792:Basic Helix-Loop-Helix Proteins; D003959:Diamines; D017382:Reactive Oxygen Species; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D012097:Repressor Proteins; D013844:Thiazoles; D000072056:Transcription Factor HES-1; C000612000:24-diamino-5-phenylthiazole; C489735:Hes1 protein, rat; C082692:Hes2 protein, rat; C489686:Hes5 protein, rat
keywords: Ductus arteriosus; Notch signaling; remodeling