Rap1 GTPase Inhibits Tumor Necrosis Factor-α-Induced Choroidal Endothelial Migration via NADPH Oxidase- and NF-κB-Dependent Activation of Rac1
| Autor: | Erika S. Wittchen, Lori Fotheringham, Haibo Wang, M. Elizabeth Hartnett |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
rac1 GTP-Binding Protein
Pathology and Forensic Medicine chemistry.chemical_compound Cell Movement medicine Animals Cells Cultured chemistry.chemical_classification Reactive oxygen species NADPH oxidase biology Choroid Tumor Necrosis Factor-alpha Neuropeptides NF-kappa B Endothelial Cells NADPH Oxidases NF-κB Regular Article NFKB1 eye diseases Choroidal Neovascularization Up-Regulation Enzyme Activation Mice Inbred C57BL Choroidal neovascularization chemistry Apocynin biology.protein Cancer research cardiovascular system Tumor necrosis factor alpha Female P22phox sense organs medicine.symptom Reactive Oxygen Species Signal Transduction |
| Zdroj: | The American journal of pathology. 185(12) |
| ISSN: | 1525-2191 |
| Popis: | Macrophage-derived tumor necrosis factor (TNF)-α has been found in choroidal neovascularization (CNV) surgically removed from patients with age-related macular degeneration. However, the role of TNF-α in CNV development remains unclear. In a murine laser-induced CNV model, compared with un-lasered controls, TNF-α mRNA was increased in retinal pigment epithelial and choroidal tissue, and TNF-α colocalized with lectin-stained migrating choroidal endothelial cells (CECs). Inhibition of TNF-α with a neutralizing antibody reduced CNV volume and reactive oxygen species (ROS) level around CNV. In CECs, pretreatment with the antioxidant apocynin or knockdown of p22phox, a subunit of NADPH oxidase, inhibited TNF-α–induced ROS generation. Apocynin reduced TNF-α–induced NF-κB and Rac1 activation, and inhibited TNF-α–induced CEC migration. TNF-α–induced Rac1 activation and CEC migration were inhibited by NF-κB inhibitor Bay11-7082. Overexpression of Rap1a prevented TNF-α–induced ROS generation and reduced NF-κB and Rac1 activation. Activation of Rap1 by 8-(4-chlorophenylthio)adenosine-2′-O-Me-cAMP prevented TNF-α–induced CEC migration and reduced laser-induced CNV volume, ROS generation, and activation of NF-κB and Rac1. These findings provide evidence that active Rap1a inhibits TNF-α–induced CEC migration by inhibiting NADPH oxidase-dependent NF-κB and Rac1 activation and suggests that Rap1a de-escalates CNV development by interfering with ROS-dependent signaling in several steps of the pathogenic process. |
| Databáze: | OpenAIRE |
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