| First Author | Wang H | Year | 2015 |
| Journal | Am J Pathol | Volume | 185 |
| Issue | 12 | Pages | 3316-25 |
| PubMed ID | 26476350 | Mgi Jnum | J:227861 |
| Mgi Id | MGI:5703690 | Doi | 10.1016/j.ajpath.2015.08.017 |
| Citation | Wang H, et al. (2015) Rap1 GTPase Inhibits Tumor Necrosis Factor-alpha-Induced Choroidal Endothelial Migration via NADPH Oxidase- and NF-kappaB-Dependent Activation of Rac1. Am J Pathol 185(12):3316-25 |
| abstractText | Macrophage-derived tumor necrosis factor (TNF)-alpha has been found in choroidal neovascularization (CNV) surgically removed from patients with age-related macular degeneration. However, the role of TNF-alpha in CNV development remains unclear. In a murine laser-induced CNV model, compared with un-lasered controls, TNF-alpha mRNA was increased in retinal pigment epithelial and choroidal tissue, and TNF-alpha colocalized with lectin-stained migrating choroidal endothelial cells (CECs). Inhibition of TNF-alpha 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-alpha-induced ROS generation. Apocynin reduced TNF-alpha-induced NF-kappaB and Rac1 activation, and inhibited TNF-alpha-induced CEC migration. TNF-alpha-induced Rac1 activation and CEC migration were inhibited by NF-kappaB inhibitor Bay11-7082. Overexpression of Rap1a prevented TNF-alpha-induced ROS generation and reduced NF-kappaB and Rac1 activation. Activation of Rap1 by 8-(4-chlorophenylthio)adenosine-2'-O-Me-cAMP prevented TNF-alpha-induced CEC migration and reduced laser-induced CNV volume, ROS generation, and activation of NF-kappaB and Rac1. These findings provide evidence that active Rap1a inhibits TNF-alpha-induced CEC migration by inhibiting NADPH oxidase-dependent NF-kappaB and Rac1 activation and suggests that Rap1a de-escalates CNV development by interfering with ROS-dependent signaling in several steps of the pathogenic process. |
