title: Downregulated bone morphogenetic protein signaling in nitrofen-induced congenital diaphragmatic hernia.
abstract: OBJECTIVE
  Bone morphogenetic proteins (BMP) have been shown to play crucial roles in not only lung and heart development, but also in the pathogenesis of pulmonary vascular remodeling in pulmonary hypertension (PH). We therefore hypothesized that BMP signaling could be altered in nitrofen-induced congenital diaphragmatic hernia (CDH) and associated PH.
  
  
  METHODS
  Pregnant rats were exposed to either 100 mg nitrofen or vehicle on embryonic day (E) 9.5. On E17 and E21, fetuses were delivered by cesarean section, killed and checked for left-sided CDH. The tissue was then harvested for pathobiological evaluation.
  
  
  RESULTS
  In nitrofen-induced CDH, pulmonary expressions of BMP4, BMP receptor (BMPR) type 2 and Id1 decreased on E17 and E21. On E17, pulmonary gremlin-1 expression increased, while BMP7 decreased. In the lungs, Id1 expression was correlated to BMP4 and BMPR2 and inversely correlated to gremlin-1 expression. Myocardial expressions of BMPR2, BMPR1A, BMP7 and SERCA-2A decreased, while gremlin-1 and noggin expressions increased on E17. On E21, myocardial expressions of Id1 and SERCA-2A decreased, while gremlin-1 expression increased. Moreover, BMPR2 and BMPR1A expressions were correlated to SERCA-2A expression and inversely correlated to pro-apoptotic Bax/Bcl2 ratio within the myocardium.
  
  
  CONCLUSIONS
  Downregulation of BMP signaling seems to contribute to pulmonary and myocardial anomalies observed in nitrofen-induced CDH.
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, 808, Lennik Road, 1070, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Makanga
authors.forename: Céline
authors.initials: C
authors.lastname: Dewachter
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Maruyama
authors.forename: Aline
authors.initials: A
authors.lastname: Vuckovic
authors.forename: Benoit
authors.initials: B
authors.lastname: Rondelet
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.forename: Laurence
authors.initials: L
authors.lastname: Dewachter
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D015536:Down-Regulation; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000378:metabolism; D065630:Hernias, Diaphragmatic, Congenital; D010647:Phenyl Ethers / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D010647:Phenyl Ethers; C007350:nitrofen