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CLIC4/Arf6 pathway – a new lead in BMPRII inhibition in pulmonary hypertension

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Title: CLIC4/Arf6 pathway – a new lead in BMPRII inhibition in pulmonary hypertension
Authors: Abdul-Salam, V
Russomanno, G
Chien-Nien, C
Mahomed, A
Yates, L
Wilkins, M
Zhao, L
Gierula, M
Dubois, O
Schaeper, U
Endruschat, J
Wojciak-Stothard, B
Item Type: Journal Article
Abstract: Rationale: Increased expression of CLIC4 (chloride intracellular channel 4) is a feature of endothelial dysfunction in pulmonary arterial hypertension, but its role in disease pathology is not fully understood. Objective: To identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension. Methods and Results: Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells identified regulators of endosomal trafficking, including Arf6 (ADP ribosylation factor 6) GTPase activating proteins and clathrin, while CLIC4 overexpression affected protein regulators of vesicular trafficking, lysosomal function, and inflammation. CLIC4 reduced BMPRII (bone morphogenetic protein receptor II) expression and signaling as a result of Arf6-mediated reduction in gyrating clathrin and increased lysosomal targeting of the receptor. BMPRII expression was restored by Arf6 siRNA, Arf inhibitor Sec7 inhibitor H3 (SecinH3), and inhibitors of clathrin-mediated endocytosis but was unaffected by chloride channel inhibitor, indanyloxyacetic acid 94 or Arf1 siRNA. The effects of CLIC4 on NF-κB (nuclear factor-kappa B), HIF (hypoxia-inducible factor), and angiogenic response were prevented by Arf6 siRNA and SecinH3. Sugen/hypoxia mice and monocrotaline rats showed elevated expression of CLIC4, activation of Arf6 and NF-κB, and reduced expression of BMPRII in the lung. These changes were established early during disease development. Lung endothelium–targeted delivery of CLIC4 siRNA or treatment with SecinH3 attenuated the disease, reduced CLIC4/Arf activation, and restored BMPRII expression in the lung. Endothelial colony–forming cells from idiopathic pulmonary hypertensive patients showed upregulation of CLIC4 expression and Arf6 activity, suggesting potential importance of this pathway in the human condition. Conclusions: Arf6 is a novel effector of CLIC4 and a new therapeutic target in pulmonary hypertension.
Issue Date: 1-Jan-2019
Date of Acceptance: 12-Oct-2018
URI: http://hdl.handle.net/10044/1/65528
DOI: https://dx.doi.org/10.1161/CIRCRESAHA.118.313705
ISSN: 0009-7330
Publisher: American Heart Association
Start Page: 52
End Page: 65
Journal / Book Title: Circulation Research
Volume: 124
Issue: 1
Copyright Statement: © 2018 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: PG/15/69/31719
Keywords: Arf
chloride channel
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
Cardiovascular System & Hematology
Publication Status: Published
Online Publication Date: 2018-10-15
Appears in Collections:Department of Medicine (up to 2019)