title: miR-17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia-Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation.
abstract: Previously we found that smooth muscle cell (SMC)-specific knockout of miR-17~92 attenuates hypoxia-induced pulmonary hypertension. However, the mechanism underlying miR-17~92-mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR-17~92 regulates hypoxia-inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs).
  
  
  
  We show that hypoxic sm-17~92-/-mice have decreased hematocrit, red blood cell counts, and hemoglobin contents. The sm-17~92-/-mouse lungs express decreased mRNA levels of HIF targets and increased levels of PHD2. miR-17~92 inhibitors suppress hypoxia-induced levels of HIF1α, VEGF, Glut1, HK2, and PDK1 but not HIF2α in vitro in PASMC. Overexpression of miR-17 in PASMC represses PHD2 expression, whereas miR-17/20a inhibitors induce PHD2 expression. The 3'-UTR of PHD2 contains a functional miR-17/20a seed sequence. Silencing of PHD2 induces HIF1α and PCNA protein levels, whereas overexpression of PHD2 decreases HIF1α and cell proliferation. SMC-specific knockout of PHD2 enhances hypoxia-induced vascular remodeling and exacerbates established pulmonary hypertension in mice. PHD2 activator R59949 reverses vessel remodeling in existing hypertensive mice. PHDs are dysregulated in PASMC isolated from pulmonary arterial hypertension patients.
  
  
  
  Our results suggest that PHD2 is a direct target of miR-17/20a and that miR-17~92 contributes to PASMC proliferation and polycythemia by suppression of PHD2 and induction of HIF1α.
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL.
authors.forename: Tianji
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL.
authors.forename: Melike
authors.initials: M
authors.lastname: Bozkanat
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL.|Children's Hospital University of Illinois, University of Illinois Hospital and Health Sciences System, Chicago, IL.
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL guofei@uic.edu.
authors.forename: Guofei
authors.initials: G
authors.lastname: Zhou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle; D011651:Pulmonary Artery / Q000166:cytology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D066253:Vascular Remodeling / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C532375:Mirn20 microRNA, mouse; D012333:RNA, Messenger; C490190:EGLN1 protein, human; C447780:EGLN2 protein, human; C488894:EGLN3 protein, human; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: hypoxia; hypoxia‐inducible factor 1; miR‐17˜92; prolyl hydroxylase 2; pulmonary artery smooth muscle cell; pulmonary hypertension; smooth muscle cell