title: Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.
abstract: BACKGROUND
  Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodeled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension. CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of pulmonary arterial hypertension.
  
  
  RESULTS
  CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, whereas CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension attenuated the abnormal angiogenic behavior that characterizes these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilization of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1.
  
  
  CONCLUSIONS
  Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.
authors: Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK (B.W.-S., V.B.A.-S., K.H.L., H.T., R.J.E., C.J.R., J.W., L.Z., M.R.W.); Cardiovascular Pulmonary Research Group, University of Colorado Denver Health Sciences Center, Aurora (D.C.I., C.L., Z.L., K.R.S.); Division of Nephrology, Department of Internal Medicine, St. Louis University, St. Louis MO (J.C.E.); Laboratory of Cancer Biology & Genetics, Centre for Cancer Research, Bethesda, MD (S.H.Y.); and National Pulmonary Hypertension Service and National Heart & Lung Institute, Imperial College Healthcare NHS Trust, London, UK (L.S.H., J.S.R.G.).
authors: Beata
authors: B
authors: Wojciak-Stothard
authors: Vahitha B
authors: VB
authors: Abdul-Salam
authors: Ka Hou
authors: KH
authors: Lao
authors: Hilda
authors: H
authors: Tsang
authors: David C
authors: DC
authors: Irwin
authors: Christina
authors: C
authors: Lisk
authors: Zoe
authors: Z
authors: Loomis
authors: Kurt R
authors: KR
authors: Stenmark
authors: John C
authors: JC
authors: Edwards
authors: Stuart H
authors: SH
authors: Yuspa
authors: Luke S
authors: LS
authors: Howard
authors: Robert J
authors: RJ
authors: Edwards
authors: Christopher J
authors: CJ
authors: Rhodes
authors: J Simon R
authors: JS
authors: Gibbs
authors: John
authors: J
authors: Wharton
authors: Lan
authors: L
authors: Zhao
authors: Martin R
authors: MR
authors: Wilkins
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000503:physiopathology*; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000166:cytology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA / Q000502:physiology
chemical_list: C479423:CLIC protein, mouse; C464459:CLIC4 protein, human; D018118:Chloride Channels; C467578:Clic4 protein, rat; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D051996:Transcription Factor RelA
keywords: angiogenesis inducing agents; endothelium; hypertension, pulmonary; hypoxia-inducible factor 1; nuclear factor-kappaB