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CLIC4/Arf6 Pathway.

Vahitha B Abdul-Salam1, Giusy Russomanno1, Chen Chien-Nien1

  • 1From the Centre for Pharmacology and Therapeutics (V.B.A.-S., G.R., C.C.-N., A.S.M., M.R.W., L.Z., M.G., O.D., B.W.-S.), Department of Medicine, Imperial College London, United Kingdom.

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|December 25, 2018
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Summary
This summary is machine-generated.

Chloride intracellular channel 4 (CLIC4) drives pulmonary hypertension by activating ADP ribosylation factor 6 (Arf6), leading to reduced bone morphogenetic protein receptor II (BMPRII) signaling. Targeting Arf6 offers a novel therapeutic strategy for pulmonary hypertension.

Keywords:
chloride channelsendocytosisendothelial cellsendothelial progenitor cellshypertension, pulmonary

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Area of Science:

  • Cardiovascular Research
  • Cell Biology
  • Molecular Medicine

Background:

  • Increased chloride intracellular channel 4 (CLIC4) expression is linked to endothelial dysfunction in pulmonary arterial hypertension (PAH).
  • The precise role of CLIC4 in PAH pathogenesis remains incompletely understood.

Purpose of the Study:

  • To identify proteins that interact with CLIC4.
  • To investigate CLIC4's downstream effectors.
  • To evaluate therapeutic strategies targeting CLIC4 signaling in PAH.

Main Methods:

  • Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells.
  • Overexpression of CLIC4 and assessment of its impact on vesicular trafficking, lysosomal function, and inflammation.
  • In vivo studies using Sugen/hypoxia mice and monocrotaline rats.
  • Evaluation of therapeutic interventions including siRNA and small molecule inhibitors.

Main Results:

  • CLIC4 interacts with regulators of endosomal trafficking, including ADP ribosylation factor 6 (Arf6) GTPase activating proteins and clathrin.
  • CLIC4 overexpression reduces bone morphogenetic protein receptor II (BMPRII) expression and signaling via Arf6-mediated mechanisms.
  • Arf6 inhibition, Arf inhibitor SecinH3, and clathrin-mediated endocytosis inhibitors restored BMPRII expression.
  • CLIC4's effects on NF-κB, HIF, and angiogenic responses were abrogated by Arf6 siRNA and SecinH3.
  • Elevated CLIC4, Arf6, and NF-κB, with reduced BMPRII, were observed in preclinical PAH models and human PAH endothelial cells.
  • Therapeutic targeting of CLIC4/Arf6 signaling attenuated disease progression in animal models.

Conclusions:

  • ADP ribosylation factor 6 (Arf6) is identified as a novel effector of CLIC4.
  • Arf6 represents a promising new therapeutic target for pulmonary hypertension.
  • The CLIC4-Arf6-BMPRII pathway is crucial in PAH development and progression.