O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature - PubMed (original) (raw)

Review

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Victor V Lima et al. Am J Physiol Regul Integr Comp Physiol. 2011 Feb.

Abstract

Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET(A) and ET(B) receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed.

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Figures

Fig. 1.

Fig. 1.

Signaling pathways activated by endothelin-1 (ET-1) in vascular smooth muscle cells (VSMC). Recognition of ET-1 by the ETA and ETB receptors in VSMCs activates intracellular signaling pathways and cascades that result in rapid alterations in cell activity and function and initiates transcriptional responses. Highlighted in the figure is the activation of PKC, MAPKs, and RhoA/Rho kinase signaling pathways, with subsequent effects on intracellular Ca2+ and calmodulin-dependent pathways as well as Ca2+-independent pathways. IP3, inositol 1,4,5-trisphosphate; SRC, sarcoma; P, phosphorylation; Pyk2, proline-rich tyrosine kinase-2; GDI, GDP dissociation inhibitors; MEK, MAPK kinase; MLC, myosin light chain; IP3R, IP3, repector; SR, sarcoplasmic reticulum.

Fig. 2.

Fig. 2.

Hexosamine biosynthetic pathway (HBP). Enzymes involved in the synthesis of uridine-diphosphate-_O_-GlcNAcylation (UDP-_O_-GlcNAc) from glucose and glucosamine and the _O_-GlcNAc modification of proteins are shown. Depicted in the figure is the interplay between _O_-GlcNAc and _O_-phosphorylation.

Fig. 3.

Fig. 3.

Proteins of signaling pathways activated by ET-1 are targets for _O_-GlcNAc. Indicated in the figure are signaling proteins that play an important role in the vascular effects by ET-1 and that are subject to the posttranslational modification by _O_-GlcNAc (please refer to the text for more details and Fig. 1 for abbreviations). G, targets of GlcNAcylation.

Fig. 4.

Fig. 4.

A: ET-1 increases the content of _O_-GlcNAc-proteins in rat aorta after 24-h incubation. Top: representative Western blot image of _O_-GlcNAc-proteins. Bottom: corresponding bar graphs showing the relative _O_-GlcNAc-proteins after normalization to β-actin expression. Results are presented as means ± SE for n = 6 in each experimental group. *P < 0.05 vs. control. B: ET-1 effects on _O_-GlcNAc protein levels are not observed when vessels were previously incubated with a selective β-_N_-acetylglucosaminidase (OGT) inhibitor. Phase contrast microscopy demonstrating that ET-1 increases _O_-GlcNAc-proteins in vascular smooth muscle cells (in culture). Previous incubation (3 h) of cells with an OGT inhibitor (3-[2-adamantanylethyl]-2-[4-chlorophenylazamethylene]-4-oxo-1,3-thiazaperhyd roine-6-carboxylic acid; 100 μmol/l) abrogates ET-1 effects on _O_-GlcNAc levels. Blue, DAPI stained nuclei; green, _O_-GlcNAc-modified proteins [FITC-labeled second antibody (anti-mouse IgG) and primary anti-_O_-GlcNAc antibody]. _O_-GlcNAc levels, before (top) and after PugNAc stimulation (bottom). Magnification, ×20.

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