title: Ghrelin ameliorates hypoxia-induced pulmonary hypertension via phospho-GSK3 β/β-catenin signaling in neonatal rats.
abstract: Effective treatment and/or prevention strategies for neonatal persistent pulmonary hypertension of the newborn (PPHN) have been an important topic in neonatal medicine. However, mechanisms of impaired pulmonary vascular structure in hypoxia-induced PPHN are poorly understood and consequently limit the development of effective treatment. In this study, we aimed to explore the molecular signaling cascades in the lungs of a PPHN animal model and used primary cultured rat pulmonary microvascular endothelial cells to analyze the physiological benefits of ghrelin during the pathogenesis of PPHN. Randomly selected newborn rats were exposed to hypoxia (10-12%) or room air and received daily s.c. injections of ghrelin (150 μg/kg) or saline. After 2 weeks, pulmonary hemodynamics and morphometry were assessed in the rats. Compared with the control, hypoxia increased pulmonary arterial pressure, right ventricle (RV) hypertrophy, and arteriolar wall thickness. Ghrelin treatment reduced both the magnitude of PH and the RV/(left ventricle+septum (Sep)) weight ratio. Ghrelin protected neonatal rats from hypoxia-induced PH via the upregulation of phosphorylation of glycogen synthase kinase 3β (p-GSK3β)/β-catenin signaling and associated with β-catenin translocation to the nucleus in the presence of growth hormone secretagogue receptor-1a. Our findings suggest that s.c. administration of ghrelin improved PH and attenuated pulmonary vascular remodeling after PPHN. These beneficial effects may be mediated by the regulation of p-GSK3β/β-catenin expression. We propose ghrelin as a novel potential therapeutic agent for PPHN.
authors.affiliation: Department of Neonatology, The Children's Hospital, Zhejiang University School of Medicine and Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, Hangzhou 310003, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Xu
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Zhu
authors.forename: Fen
authors.initials: F
authors.lastname: Cheng
authors.forename: Ke-Wen
authors.initials: KW
authors.lastname: Jiang
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Gu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shen
authors.forename: Yi-Dong
authors.initials: YD
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Li-Zhong
authors.initials: LZ
authors.lastname: Du
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000494:pharmacology* / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D007231:Infant, Newborn; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010547:Persistent Fetal Circulation Syndrome / Q000209:etiology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000199:Actins; D054439:Ghrelin; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D054440:Receptors, Ghrelin; D051176:beta Catenin; C498862:Acta2 protein, rat; C000605506:GSK3B protein, human; C000605508:Gsk3b protein, rat