Adam C. Straub, Katherine A. Clark, Mark A. Ross, Ashwin G. Chandra, Song Li, Xiang Gao, Patrick J. Pagano, Donna B. Stolz, Aaron Barchowsky
J Clin Invest.
2008;
118(12):3980–3989
doi:10.1172/JCI35092
This article Copyright © 2008, The American Society for Clinical Investigation
Abstract
|
Full text
|
PDF
E
nvironmental 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 cell-permeant 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.
This file is in Adobe Acrobat (PDF) format.
If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not
allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users:
Right-click on the Download link and choose the option that says something like "Save Link As...".
Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you
configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can
usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.