| First Author | Vikram A | Year | 2014 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 34 |
| Issue | 10 | Pages | 2301-9 |
| PubMed ID | 25147340 | Mgi Jnum | J:318252 |
| Mgi Id | MGI:6858926 | Doi | 10.1161/ATVBAHA.114.304338 |
| Citation | Vikram A, et al. (2014) Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc-regulated reactive oxygen species. Arterioscler Thromb Vasc Biol 34(10):2301-9 |
| abstractText | OBJECTIVE: Reactive oxygen species regulate canonical Wnt signaling. However, the role of the redox regulatory protein p66(Shc) in the canonical Wnt pathway is not known. We investigated whether p66(Shc) is essential for canonical Wnt signaling in the endothelium and determined whether the canonical Wnt pathway induces vascular endothelial dysfunction via p66(Shc)-mediated oxidative stress. APPROACH AND RESULTS: The canonical Wnt ligand Wnt3a induced phosphorylation (activation) of p66(Shc) in endothelial cells. Wnt3a-stimulated dephosphorylation of beta-catenin, and beta-catenin-dependent transcription, was inhibited by knockdown of p66(Shc). Exogenous H2O2-induced beta-catenin dephosphorylation was also mediated by p66(Shc). Moreover, p66(Shc) overexpression dephosphorylated beta-catenin and increased beta-catenin-dependent transcription, independent of Wnt3a ligand. P66(Shc)-induced beta-catenin dephosphorylation was inhibited by antioxidants N-acetyl cysteine and catalase. Wnt3a upregulated endothelial NADPH oxidase-4, and beta-catenin dephosphorylation was suppressed by knocking down NADPH oxidase-4 and by antioxidants. Wnt3a increased H2O2 levels in endothelial cells and impaired endothelium-dependent vasorelaxation in mouse aortas, both of which were rescued by p66(Shc) knockdown. P66(Shc) knockdown also inhibited adhesion of monocytes to Wnt3a-stimulated endothelial cells. Furthermore, constitutively active beta-catenin expression in the endothelium increased vascular reactive oxygen species and impaired endothelium-dependent vasorelaxation. In vivo, high-fat diet feeding-induced endothelial dysfunction in mice was associated with increased endothelial Wnt3a, dephosphorylated beta-catenin, and phosphorylated p66(Shc). High-fat diet-induced dephosphorylation of endothelial beta-catenin was diminished in mice in which p66(Shc) was knocked down. CONCLUSIONS: p66(Shc) plays a vital part in canonical Wnt signaling in the endothelium and mediates Wnt3a-stimulated endothelial oxidative stress and dysfunction. |
