Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide
Straub, AC; Clark, KA; Ross, MA; Chandra, AG; Li, S; Gao, X; Pagano, PJ; Stolz, DB; Barchowsky, A
HERO ID
620260
Reference Type
Journal Article
Year
2008
Language
English
PMID
| HERO ID | 620260 |
|---|---|
| In Press | No |
| Year | 2008 |
| Title | Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide |
| Authors | Straub, AC; Clark, KA; Ross, MA; Chandra, AG; Li, S; Gao, X; Pagano, PJ; Stolz, DB; Barchowsky, A |
| Journal | Journal of Clinical Investigation |
| Volume | 118 |
| Issue | 12 |
| Page Numbers | 3980-3989 |
| Abstract | Environmental arsenic exposure, through drinking contaminated water, is a significant risk factor for developing vascular diseases and is associated with liver portal hypertension, vascular shunting, and portal fibrosis through unknown mechanisms. We found that the addition of low doses of arsenite to the drinking water of mice resulted in marked pathologic remodeling in liver sinusoidal endothelial cells (SECs), including SEC defenestration, capillarization, increased junctional PECAM-1 expression, protein nitration, and decreased liver clearance of modified albumin. Furthermore, the pathologic changes observed after in vivo exposure were recapitulated in isolated mouse SECs exposed to arsenic in culture. To investigate the role of NADPH oxidase-generated ROS in this remodeling, we examined the effect of arsenite in the drinking water of mice deficient for the p47 subunit of the NADPH oxidase and found that knockout mice were protected from arsenite-induced capillarization and protein nitration. Furthermore, ex vivo arsenic exposure increased SEC superoxide generation, and this effect was inhibited by addition of a Nox2 inhibitor and quenched by the cellpermeant superoxide scavenger. In addition, inhibiting either oxidant generation or Rac1-GTPase blocked ex vivo arsenic-stimulated SEC differentiation and dysfunction. Our data indicate that a Nox2-based oxidase is required for SEC capillarization and that it may play a central role in vessel remodeling following environmentally relevant arsenic exposures. [ABSTRACT FROM AUTHOR] Copyright of Journal of Clinical Investigation is the property of American Society for Clinical Investigation and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts) |
| Doi | 10.1172/JCI35092 |
| Pmid | 19033667 |
| Wosid | WOS:000261237300020 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | |WOS:000261237300020 |
| Is Public | Yes |
| Language Text | English |
| Is Peer Review | Yes |