title: O-linked β-N-acetylglucosamine transferase directs cell proliferation in idiopathic pulmonary arterial hypertension.
abstract: BACKGROUND
  Idiopathic pulmonary arterial hypertension (IPAH) is a cardiopulmonary disease characterized by cellular proliferation and vascular remodeling. A more recently recognized characteristic of the disease is the dysregulation of glucose metabolism. The primary link between altered glucose metabolism and cell proliferation in IPAH has not been elucidated. We aimed to determine the relationship between glucose metabolism and smooth muscle cell proliferation in IPAH.
  
  
  RESULTS
  Human IPAH and control patient lung tissues and pulmonary artery smooth muscle cells (PASMCs) were used to analyze a specific pathway of glucose metabolism, the hexosamine biosynthetic pathway. We measured the levels of O-linked β-N-acetylglucosamine modification, O-linked β-N-acetylglucosamine transferase (OGT), and O-linked β-N-acetylglucosamine hydrolase in control and IPAH cells and tissues. Our data suggest that the activation of the hexosamine biosynthetic pathway directly increased OGT levels and activity, triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-linked β-N-acetylglucosamine modification levels and abrogated PASMC proliferation. The increased proliferation observed in IPAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1.
  
  
  CONCLUSIONS
  Our data demonstrate that hexosamine biosynthetic pathway flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of host cell factor-1. These findings establish a novel regulatory role for OGT in IPAH, shed a new light on our understanding of the disease pathobiology, and provide opportunities to design novel therapeutic strategies for IPAH.
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Jarrod W
authors: JW
authors: Barnes
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Liping
authors: L
authors: Tian
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Gustavo A
authors: GA
authors: Heresi
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Carol F
authors: CF
authors: Farver
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Kewal
authors: K
authors: Asosingh
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Suzy A A
authors: SA
authors: Comhair
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.
authors: Kulwant S
authors: KS
authors: Aulak
authors: From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH. dweikr@ccf.org.
authors: Raed A
authors: RA
authors: Dweik
mesh_terms: D000328:Adult; D000496:Alloxan / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D018450:Disease Progression; D065627:Familial Primary Pulmonary Hypertension / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D005260:Female; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006595:Hexosamines / Q000096:biosynthesis; D006760:Hospitalization / Q000706:statistics & numerical data; D051863:Host Cell Factor C1 / Q000502:physiology; D006801:Humans; D016040:Lung Transplantation / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011651:Pulmonary Artery / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C497692:HCFC1 protein, human; D006595:Hexosamines; D051863:Host Cell Factor C1; D000496:Alloxan; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D005947:Glucose
keywords: UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; biosynthetic pathways; hexosamines; host cell factor C1; pulmonary hypertension; smooth muscle