Journal article
Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc-regulated reactive oxygen species
Arteriosclerosis, thrombosis, and vascular biology, Vol.34(10), pp.2301-2309
10/2014
DOI: 10.1161/ATVBAHA.114.304338
PMCID: PMC6069972
PMID: 25147340
Abstract
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.
The canonical Wnt ligand Wnt3a induced phosphorylation (activation) of p66(Shc) in endothelial cells. Wnt3a-stimulated dephosphorylation of β-catenin, and β-catenin-dependent transcription, was inhibited by knockdown of p66(Shc). Exogenous H2O2-induced β-catenin dephosphorylation was also mediated by p66(Shc). Moreover, p66(Shc) overexpression dephosphorylated β-catenin and increased β-catenin-dependent transcription, independent of Wnt3a ligand. P66(Shc)-induced β-catenin dephosphorylation was inhibited by antioxidants N-acetyl cysteine and catalase. Wnt3a upregulated endothelial NADPH oxidase-4, and β-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 β-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 β-catenin, and phosphorylated p66(Shc). High-fat diet-induced dephosphorylation of endothelial β-catenin was diminished in mice in which p66(Shc) was knocked down.
p66(Shc) plays a vital part in canonical Wnt signaling in the endothelium and mediates Wnt3a-stimulated endothelial oxidative stress and dysfunction.
Details
- Title: Subtitle
- Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc-regulated reactive oxygen species
- Creators
- Ajit Vikram - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.). ajit-vikram@uiowa.edu kaikobad-irani@uiowa.eduYoung-Rae Kim - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Santosh Kumar - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Asma Naqvi - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Timothy A Hoffman - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Ajay Kumar - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Francis J Miller Jr - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Cuk-Seong Kim - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.)Kaikobad Irani - From the Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (A.V., Y.-R.K., S.K., F.J.M., K.I.); Cardiovascular Institute, University of Pittsburgh, PA (A.N., A.K.); Department of Biochemistry and Molecular Biology, University of Louisville, KY (T.A.H.); and Department of Physiology, Chungnam National University, Daejeon, Korea (C.-S.K.). ajit-vikram@uiowa.edu kaikobad-irani@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.34(10), pp.2301-2309
- Publisher
- United States
- DOI
- 10.1161/ATVBAHA.114.304338
- PMID
- 25147340
- PMCID
- PMC6069972
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Grant note
- R01 HL070929 / NHLBI NIH HHS R21 HL098892 / NHLBI NIH HHS R01 HL094959 / NHLBI NIH HHS
- Language
- English
- Date published
- 10/2014
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984047997102771
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