RGD Reference Report - O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway. - Rat Genome Database

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O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway.

Authors: Lima, VV  Giachini, FR  Carneiro, FS  Carvalho, MH  Fortes, ZB  Webb, RC  Tostes, RC 
Citation: Lima VV, etal., Cardiovasc Res. 2011 Feb 15;89(3):614-22. doi: 10.1093/cvr/cvq338. Epub 2010 Oct 26.
RGD ID: 9590186
Pubmed: PMID:20978008   (View Abstract at PubMed)
PMCID: PMC3028974   (View Article at PubMed Central)
DOI: DOI:10.1093/cvr/cvq338   (Journal Full-text)

AIMS: Glycosylation with beta-N-acetylglucosamine (O-GlcNAcylation) is one of the most complex post-translational modifications. The cycling of O-GlcNAc is controlled by two enzymes: UDP-NAc transferase (OGT) and O-GlcNAcase (OGA). We recently reported that endothelin-1 (ET-1) augments vascular levels of O-GlcNAcylated proteins. Here we tested the hypothesis that O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway. METHODS AND RESULTS: Incubation of vascular smooth muscle cells (VSMCs) with ET-1 (0.1 muM) produces a time-dependent increase in O-GlcNAc levels. ET-1-induced O-GlcNAcylation is not observed when VSMCs are previously transfected with OGT siRNA, treated with ST045849 (OGT inhibitor) or atrasentan (ET(A) antagonist). ET-1 as well as PugNAc (OGA inhibitor) augmented contractions to phenylephrine in endothelium-denuded rat aortas, an effect that was abolished by the Rho kinase inhibitor Y-27632. Incubation of VSMCs with ET-1 increased expression of the phosphorylated forms of myosin phosphatase target subunit 1 (MYPT-1), protein kinase C-potentiated protein phosphatase 1 inhibitor protein (protein kinase C-potentiated phosphatase inhibitor-17), and myosin light chain (MLC) and RhoA expression and activity, and this effect was abolished by both OGT siRNA transfection or OGT inhibition and atrasentan. ET-1 also augmented expression of PDZ-Rho GEF (guanine nucleotide exchange factor) and p115-Rho GEF in VSMCs and this was prevented by OGT siRNA, ST045849, and atrasentan. CONCLUSION: We suggest that ET-1 augments O-GlcNAcylation and this modification contributes to increased vascular contractile responses via activation of the RhoA/Rho-kinase pathway.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
OgtRatpositive regulation of gene expression  IMP  RGD 
OgtRatpositive regulation of protein phosphorylation  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ogt  (O-linked N-acetylglucosamine (GlcNAc) transferase)


Additional Information