ArticleCirculation research2019
CLIC4/Arf6 Pathway.
Article in Circulation research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 53 citations in OpenAlex.
- RELM-β Augmented Hypoxia-Induced Pulmonary Hypertension Through Interacting with GIPC1, OR1N1 and CLIC4.Cardiovascular drugs and therapy · 2026Article
- Single-nucleus RNA sequencing identifies conserved structural cell programs in allergic lung inflammation.The journal of allergy and clinical immunology. Global · 2026Article
- Genetic determinants of insufficiency of the collateral circulation.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- Spectrum and functions of ion channels and transporters in osteoclasts.Bone research · 2026Review
- Role of Perturbations of Epigenetic Processes in Cardiac Hypertrophy and Fibrotic Scarring.Current cardiology reviews · 2026Review
- CLICs Inhibitor IAA94 Alleviates Inflammation and Injury in Septic Liver by Preventing Pyroptosis in Macrophages.Inflammation · 2025Article
- A novel tRNA‑derived small RNA, 5'tiRNA‑Gln‑TTG‑001, aggravates cardiomyocyte inflammatory injury through upregulation of CLIC4.Molecular medicine reports · 2025Article
- Methuosis key gene ARF6 as a diagnostic, prognostic and immunotherapeutic marker for prostate cancer: based on a comprehensive pan-cancer multi-omics analysis.Discover oncology · 2025Article
- Endothelial Dysfunction in Pulmonary Hypertension: Does ADP Ribosylation Factor 6-mediated HIF-2α Stabilization Matter?American journal of respiratory cell and molecular biology · 2025Article
- ARF6 as a Novel Activator of HIF-2α in Pulmonary Arterial Hypertension.American journal of respiratory cell and molecular biology · 2025Article
- Emerging Gene Therapy Based on Nanocarriers: A Promising Therapeutic Alternative for Cardiovascular Diseases and a Novel Strategy in Valvular Heart Disease.International journal of molecular sciences · 2025Review
- The causal effect of natural killer cells on COVID-19 infection, hospitalization and severity.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Article
- Intracellular Chloride Channels: A Rising Target in Lung Disease Research.Journal of respiratory biology and translational medicine · 2025Article
- Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives.Cancers · 2024Review
- RNA-binding protein DND1 participates in migration, invasion, and EMT of prostate cancer cells by degrading CLIC4.Histology and histopathology · 2024Article
- Advances in the role of ion channels in leukemia.Heliyon · 2024Review
- Chloride ions in health and disease.Bioscience reports · 2024Review
- Article
- CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and CaPhysiological reviews · 2023Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 2 countries.
Funding
Abstract
rationaleIncreased 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.
objectiveTo identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension. METHODS AND
resultsProteomic 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.
conclusionsArf6 is a novel effector of CLIC4 and a new therapeutic target in pulmonary hypertension.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.