دورية أكاديمية
CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA.
| العنوان: | CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA. |
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| المؤلفون: | Kleinjan ML; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago., Mao Y; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago., Naiche LA; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago., Joshi JC; Department of Pharmacology (J.C.J., D.M.), University of Illinois at Chicago., Gupta A; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago., Jesse JJ; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago., Shaye DD; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago., Mehta D; Department of Pharmacology (J.C.J., D.M.), University of Illinois at Chicago., Kitajewski J; Department of Physiology and Biophysics (M.L.K., D.Y.M., L.A.N., A.G., J.J.J., D.D.S., J.K.), University of Illinois at Chicago.; University of Illinois Cancer Center, Chicago (J.K.). |
| المصدر: | Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2023 Aug; Vol. 43 (8), pp. 1441-1454. Date of Electronic Publication: 2023 Jun 15. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 9505803 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4636 (Electronic) Linking ISSN: 10795642 NLM ISO Abbreviation: Arterioscler Thromb Vasc Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins Original Publication: Dallas, TX : American Heart Association, c1995- |
| مواضيع طبية MeSH: | Receptor, PAR-1*/genetics , Receptor, PAR-1*/metabolism , rhoA GTP-Binding Protein*/metabolism, Humans ; Mice ; Animals ; Thrombin/pharmacology ; Thrombin/metabolism ; Endothelium/metabolism ; Human Umbilical Vein Endothelial Cells/metabolism ; Cells, Cultured ; Chloride Channels/genetics ; Chloride Channels/metabolism ; Mitochondrial Proteins/metabolism |
| مستخلص: | Background: Endothelial CLICs (chloride intracellular channel proteins) CLIC1 and CLIC4 are required for the GPCRs (G-protein-coupled receptors) S1PR1 (sphingosine-1-phosphate receptor 1) and S1PR3 to activate the small GTPases Rac1 (Ras-related C3 botulinum toxin substrate 1) and RhoA (Ras homolog family member A). To determine whether CLIC1 and CLIC4 function in additional endothelial GPCR pathways, we evaluated CLIC function in thrombin signaling via the thrombin-regulated PAR1 (protease-activated receptor 1) and downstream effector RhoA. Methods: We assessed the ability of CLIC1 and CLIC4 to relocalize to cell membranes in response to thrombin in human umbilical vein endothelial cells (HUVEC). We examined CLIC1 and CLIC4 function in HUVEC by knocking down expression of each CLIC protein and compared thrombin-mediated RhoA or Rac1 activation, ERM (ezrin/radixin/moesin) phosphorylation, and endothelial barrier modulation in control and CLIC knockdown HUVEC. We generated a conditional murine allele of Clic4 and examined PAR1-mediated lung microvascular permeability and retinal angiogenesis in mice with endothelial-specific loss of Clic4 . Results: Thrombin promoted relocalization of CLIC4, but not CLIC1, to HUVEC membranes. Knockdown of CLIC4 in HUVEC reduced thrombin-mediated RhoA activation, ERM phosphorylation, and endothelial barrier disruption. Knockdown of CLIC1 did not reduce thrombin-mediated RhoA activity but prolonged the RhoA and endothelial barrier response to thrombin. Endothelial-specific deletion of Clic4 in mice reduced lung edema and microvascular permeability induced by PAR1 activating peptide. Conclusions: CLIC4 is a critical effector of endothelial PAR1 signaling and is required to regulate RhoA-mediated endothelial barrier disruption in cultured endothelial cells and murine lung endothelium. CLIC1 was not critical for thrombin-mediated barrier disruption but contributed to the barrier recovery phase after thrombin treatment. Competing Interests: Disclosures None. |
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| معلومات مُعتمدة: | R01 GM134032 United States GM NIGMS NIH HHS; R01 HL084153 United States HL NHLBI NIH HHS; R01 HL112626 United States HL NHLBI NIH HHS; R01 HL119043 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: RhoA GTP-binding protein; chloride intracellular channel; human umbilical vein endothelial cell; protease-activated receptor 1; thrombin |
| المشرفين على المادة: | 0 (Receptor, PAR-1) EC 3.6.5.2 (rhoA GTP-Binding Protein) EC 3.4.21.5 (Thrombin) 0 (CLIC4 protein, human) 0 (Chloride Channels) 0 (CLIC protein, mouse) 0 (Mitochondrial Proteins) |
| تواريخ الأحداث: | Date Created: 20230615 Date Completed: 20230728 Latest Revision: 20240802 |
| رمز التحديث: | 20240802 |
| مُعرف محوري في PubMed: | PMC10527476 |
| DOI: | 10.1161/ATVBAHA.123.319206 |
| PMID: | 37317855 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1524-4636 |
|---|---|
| DOI: | 10.1161/ATVBAHA.123.319206 |