The long-term objective is to understand the mechanism for the antioxidant effect of selenium against inflammation. Low Se content is associated with a higher incidence of cardiovascular diseases. The pathogenesis of atherosclerosis is recognized as a chronic inflammatory disease in endothelium, and inflammation in other organs may also increase the risk of atherogenesis. The investigators have recently found that mice deficient in two Se-dependent glutathione peroxidase (GPX) isozymes, GPX-1 and GPX-GI (encoded by Gpxl and Gpx2) develop severe colitis by the time they are weaned. Because GPX isozymes have been implicated to be the anti-atherosclerotic activity of Se, the investigators propose that the GPX-1 and GPX-GI protect against atherosclerotic lesions. In the first aim, the investigators plan to determine if GPX-1 and GPX-GI are the major anti-atherosclerotic activity of Se. They will study if mice deficient in either the Gpxl or the Gpx2 gene, or both genes, in C57BW6J background have more severe atherosclerotic lesions than the control mice. If these mice deficient in one or both of GPX isozymes no longer respond to dietary Se modulation, this suggests that the GPX isozyrnes are the major Se-dependent anti-atherosclerotic activity. If one or both GPX-1 and GPX-GI have anti-atherosclerotic activity, the investigators will distinguish this activity in the prevention of low density lipoprotein (LDL) oxidation originated from dietary and endogenous sources in the second aim. If Gpx2-knockout mice have a higher level of oxidized LDL in the plasma than control mice after being fed a high fat diet, because the Gpx2 gene is highly expressed in the intestinal epithelium, this suggests that the LDL oxidation may occur from the dietary source. If Gpxl-knockout monocytes or neutrophils can generate more oxidized LDL than control cells, this suggests that GPX-1 can prevent LDL oxidation from endogenous cells. Whether GPX-1 inhibits NF-KB activation, which plays a pivotal role in inflammatory response, will be analyzed in macrophages/monocytes. If neither GPX-1 nor GPX-GI has anti-atherosclerotic activity, or these 2 isozymes are not the major Se-dependent anti-atherosclerotic activity, it suggests other selenoproteins contribute. The investigators will generate GpxS-knockout mice deficient in the plasma GPX isozyme, GPX-P, to study this activity as they have done for Gpx2-knockout mice.
| Chu, Fong-Fong; Esworthy, R Steven; Chu, Peiguo G et al. (2004) Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res 64:962-8 |
| Esworthy, R Steven; Binder, Scott W; Doroshow, James H et al. (2003) Microflora trigger colitis in mice deficient in selenium-dependent glutathione peroxidase and induce Gpx2 gene expression. Biol Chem 384:597-607 |
