Abstract
BackgroundWe have shown that glucosamine (GlcN) or O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) treatment augments O-linked-N-acetylglucosamine (O-GlcNAc) protein modification and attenuates inflammatory mediator expression, leukocyte infiltration and neointima formation in balloon injured rat carotid arteries and have identified the arterial smooth muscle cell (SMC) as the target cell in the injury response. NFκB signaling has been shown to mediate the expression of inflammatory genes and neointima formation in injured arteries. Phosphorylation of the p65 subunit of NFκB is required for the transcriptional activation of NFκB. This study tested the hypothesis that GlcN or PUGNAc treatment protects vascular SMCs against tumor necrosis factor (TNF)-α induced inflammatory stress by enhancing O-GlcNAcylation and inhibiting TNF-α induced phosphorylation of NFκB p65, thus inhibiting NFκB signaling.Methodology/Principal FindingsQuiescent rat aortic SMCs were pretreated with GlcN (5 mM), PUGNAc (10−4 M) or vehicle and then stimulated with TNF-α (10 ng/ml). Both treatments inhibited TNF-α-induced expression of chemokines [cytokine-induced neutrophil chemoattractant (CINC)-2β and monocyte chemotactic protein (MCP)-1] and adhesion molecules [vascular cell adhesion molecule (VCAM)-1 and P-Selectin]. Both treatments inhibited TNF-α induced NFκB p65 activation and promoter activity, increased NFκB p65 O-GlcNAcylation and inhibited NFκB p65 phosphorylation at Serine 536, thus promoting IκBα binding to NFκB p65.ConclusionsThere is a reciprocal relationship between O-GlcNAcylation and phosphorylation of NFκB p65, such that increased NFκB p65 O-GlcNAc modification inhibits TNF-α-Induced expression of inflammatory mediators through inhibition of NFκB p65 signaling. These findings provide a mechanistic basis for our previous observations that GlcN and PUGNAc treatments inhibit inflammation and remodeling induced by acute endoluminal arterial injury.
Highlights
Inflammation plays an important role in the pathogenesis of many forms of vascular disease, including responses to acute vascular injury
These findings provide a mechanistic basis for our previous observations that GlcN and PUGNAc treatments inhibit inflammation and remodeling induced by acute endoluminal arterial injury
We have shown that both GlcN and PUGNAc decrease expression of chemokines [cytokineinduced neutrophil chemoattractant (CINC)-2b and monocyte chemotactic protein (MCP)-1] and adhesion molecules [P-selectin and vascular cell adhesion molecule (VCAM)-1], as well as periadventitial infiltration of neutrophils and monocyte/macrophages in the setting of acute arterial injury in the rat, and that chronic GlcN administration inhibits subsequent neointima formation
Summary
Inflammation plays an important role in the pathogenesis of many forms of vascular disease, including responses to acute vascular injury. We have shown that both GlcN and PUGNAc decrease expression of chemokines [cytokineinduced neutrophil chemoattractant (CINC)-2b and monocyte chemotactic protein (MCP)-1] and adhesion molecules [P-selectin and vascular cell adhesion molecule (VCAM)-1], as well as periadventitial infiltration of neutrophils and monocyte/macrophages in the setting of acute arterial injury in the rat, and that chronic GlcN administration inhibits subsequent neointima formation. These anti-inflammatory and vasoprotective effects are associated with increased levels of O-GlcNAc modified proteins in injured blood vessels [5]. This study tested the hypothesis that GlcN or PUGNAc treatment protects vascular SMCs against tumor necrosis factor (TNF)-a induced inflammatory stress by enhancing O-GlcNAcylation and inhibiting TNF-a induced phosphorylation of NFkB p65, inhibiting NFkB signaling
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