title: MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli.
  
  
  RESULTS
  Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21-null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH.
  
  
  CONCLUSIONS
  A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH.
authors.affiliation: Brigham and Women's Hospital, New Research Building, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Victoria N
authors.initials: VN
authors.lastname: Parikh
authors.forename: Richard C
authors.initials: RC
authors.lastname: Jin
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rabello
authors.forename: Natali
authors.initials: N
authors.lastname: Gulbahce
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.forename: Andrew
authors.initials: A
authors.lastname: Hale
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cottrill
authors.forename: Rahamthulla S
authors.initials: RS
authors.lastname: Shaik
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Zhang
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Maron
authors.forename: Jochen C
authors.initials: JC
authors.lastname: Hartner
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.forename: Albert-László
authors.initials: AL
authors.lastname: Barabási
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs