title: Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells.
abstract: This study was designed to determine whether cyclic stretch induces a persistent pulmonary hypertension of the newborn (PPHN) phenotype of increased NADPH oxidase (Nox) 4 signaling in control pulmonary artery smooth muscle cells (PASMC), and to identify the signal transduction molecules involved. To achieve this, PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and PASMC were isolated from control (twin) and PPHN lambs. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h. Stretch-induced Nox4 expression was attenuated by inhibition of mitochondrial complex III and NF-κB, and stretch-induced protein thiol oxidation was attenuated by Nox4 small interfering RNA and complex III inhibition. NF-κB activity was increased by stretch in a complex III-dependent fashion, and stretch-induced cyclin D1 expression was attenuated by complex III inhibition and Nox4 small interfering RNA. This is the first study to show that cyclic stretch increases Nox4 expression via mitochondrial complex III-induced activation of NF-κB in fetal PASMC, resulting in ROS signaling and increased cyclin D1 expression. Targeting these signaling molecules may attenuate pulmonary vascular remodeling associated with PPHN.
authors.affiliation: Department of Pediatrics, University of California Davis Medical Center, Sacramento, California; swedgwood@ucdavis.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wedgwood
authors.affiliation: Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York; and.
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrusimha
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.affiliation: Department of Pediatrics, University of California Davis Medical Center, Sacramento, California;
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010547:Persistent Fetal Circulation Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases
keywords: NADPH oxidase; pulmonary hypertension; reactive oxygen species