PMID- 28759157 OWN - NLM STAT- MEDLINE DCOM- 20180416 LR - 20211204 IS - 1099-0496 (Electronic) IS - 1099-0496 (Linking) VI - 52 IP - 11 DP - 2017 Nov TI - mTOR-Notch3 signaling mediates pulmonary hypertension in hypoxia-exposed neonatal rats independent of changes in autophagy. PG - 1443-1454 LID - 10.1002/ppul.23777 [doi] AB - BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) is a pivotal regulator of cell proliferation, survival, and autophagy. Autophagy is increased in adult experimental chronic pulmonary hypertension (PHT), but its contributory role to pulmonary vascular disease remains uncertain and has yet to be explored in the neonatal animal. Notch is a major pro-proliferative pathway activated by mTOR. A direct relationship between autophagy and Notch signaling has not been previously explored. Our aim was to examine changes in mTOR-, Notch-, and autophagy-related pathways and the therapeutic effects of autophagy modulators in experimental chronic neonatal PHT secondary to chronic hypoxia. METHODS: Rat pups were exposed to normoxia or hypoxia (13% O(2) ) from postnatal days 1-21, while receiving treatment with temsirolimus (mTOR inhibitor), DAPT (Notch inhibitor), or chloroquine (inhibitor of autophagic flux). RESULTS: Exposure to hypoxia up-regulated autophagy and Notch3 signaling markers in lung, pulmonary artery (PA), and PA-derived smooth muscle cells (SMCs). Temsirolimus prevented chronic PHT and attenuated PA and SMC signaling secondary to hypoxia. These effects were replicated by DAPT. mTOR or Notch inhibition also down-regulated smooth muscle content of platelet-derived growth factor beta-receptor, a known contributor to vascular remodeling. In contrast, chloroquine had no modifying effects on markers of chronic PHT. Knockdown of Beclin-1 in SMCs had no effect on hypoxia-stimulated Notch3 signaling. CONCLUSIONS: mTOR-Notch3 signaling plays a critical role in experimental chronic neonatal PHT. Inhibition of autophagy did not suppress Notch signaling and had no effect on markers of chronic PHT. CI - (c) 2017 Wiley Periodicals, Inc. FAU - Ivanovska, Julijana AU - Ivanovska J AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. FAU - Shah, Sparsh AU - Shah S AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. FAU - Wong, Mathew J AU - Wong MJ AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. FAU - Kantores, Crystal AU - Kantores C AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. FAU - Jain, Amish AU - Jain A AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada. FAU - Post, Martin AU - Post M AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada. FAU - Yeganeh, Behzad AU - Yeganeh B AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. FAU - Jankov, Robert P AU - Jankov RP AUID- ORCID: 0000-0002-9095-4398 AD - Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. AD - Faculty of Medicine, Department of Physiology, University of Toronto, Toronto, Ontario, Canada. AD - Molecular Biomedicine Program, Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, Ontario, Canada. AD - Faculty of Medicine, Department of Paediatrics, University of Ottawa, Ottawa, Ontario, Canada. LA - eng PT - Journal Article DEP - 20170731 PL - United States TA - Pediatr Pulmonol JT - Pediatric pulmonology JID - 8510590 RN - 0 (24-diamino-5-phenylthiazole) RN - 0 (Diamines) RN - 0 (Notch3 protein, rat) RN - 0 (Receptor, Notch3) RN - 0 (Thiazoles) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Animals, Newborn MH - Autophagy MH - Cell Proliferation/drug effects MH - Diamines/pharmacology MH - Female MH - Hypertension, Pulmonary/*metabolism MH - Hypoxia/metabolism MH - Lung/blood supply/metabolism MH - Male MH - Myocytes, Smooth Muscle/metabolism MH - Pulmonary Artery/metabolism MH - Rats, Sprague-Dawley MH - Receptor, Notch3/antagonists & inhibitors/*metabolism MH - Receptor, Platelet-Derived Growth Factor beta/*metabolism MH - Signal Transduction MH - Sirolimus/analogs & derivatives/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Thiazoles/pharmacology OTO - NOTNLM OT - neonatal pulmonary medicine OT - pulmonary hypertension OT - pulmonary vascular disorders EDAT- 2017/08/02 06:00 MHDA- 2018/04/17 06:00 CRDT- 2017/08/01 06:00 PHST- 2017/03/15 00:00 [received] PHST- 2017/07/06 00:00 [accepted] PHST- 2017/08/02 06:00 [pubmed] PHST- 2018/04/17 06:00 [medline] PHST- 2017/08/01 06:00 [entrez] AID - 10.1002/ppul.23777 [doi] PST - ppublish SO - Pediatr Pulmonol. 2017 Nov;52(11):1443-1454. doi: 10.1002/ppul.23777. Epub 2017 Jul 31.