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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Parker, William H. May, James M. Qu, Zhi-chao |
| Description | Author Affiliation: Parker WH ( From the Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303.); Qu ZC ( From the Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303.); May JM ( From the Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303 james.may@vanderbilt.edu.) |
| Abstract | Intracellular ascorbate (vitamin C) has previously been shown to tighten the endothelial barrier and maintain barrier integrity during acute inflammation in vitro. However, the downstream effectors of ascorbate in the regulation of endothelial permeability remain unclear. In this study, we evaluated ascorbate as a mediator of thrombin-induced barrier permeabilization in human umbilical vein endothelial cells and their immortalized hybridoma line, EA.hy926. We found that the vitamin fully prevented increased permeability to the polysaccharide inulin by thrombin in a dose-dependent manner, and it took effect both before and after subjection to thrombin. Thrombin exposure consumed intracellular ascorbate but not the endogenous antioxidant GSH. Likewise, the antioxidants dithiothreitol and tempol did not reverse permeabilization. We identified a novel role for ascorbate in preserving cAMP during thrombin stimulation, resulting in two downstream effects. First, ascorbate maintained the cortical actin cytoskeleton in a Rap1- and Rac1-dependent manner, thus preserving stable adherens junctions between adjacent cells. Second, ascorbate prevented actin polymerization and formation of stress fibers by reducing the activation of RhoA and phosphorylation of myosin light chain. Although ascorbate and thrombin both required calcium for their respective effects, ascorbate did not prevent thrombin permeabilization by obstructing calcium influx. However, preservation of cAMP by ascorbate was found to depend on both the production of nitric oxide by endothelial nitric-oxide synthase, which ascorbate is known to activate, and the subsequent generation cGMP by guanylate cyclase. Together, these data implicate ascorbate in the prevention of inflammatory endothelial barrier permeabilization and explain the underlying signaling mechanism. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 35 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-08-28 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Ascorbic Acid Pharmacology Cell Membrane Permeability Drug Effects Human Umbilical Vein Endothelial Cells Cytology Intracellular Space Metabolism Thrombin Actins Antigens, CD Antioxidants Cadherins Calcium Cyclic AMP Cyclic GMP Endocytosis Enzyme Activation Intercellular Junctions Models, Biological Myosin Light Chains Nitric Oxide Phosphorylation Polymerization Signal Transduction Stress Fibers Rac1 GTP-Binding Protein Rap1 GTP-Binding Proteins RhoA GTP-Binding Protein Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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