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O-GlcNAc modification of NF?B p65 inhibits TNF-?-induced inflammatory mediator expression in rat aortic smooth muscle cells.

ABSTRACT: We 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. NF?B signaling has been shown to mediate the expression of inflammatory genes and neointima formation in injured arteries. Phosphorylation of the p65 subunit of NF?B is required for the transcriptional activation of NF?B. This study tested the hypothesis that GlcN or PUGNAc treatment protects vascular SMCs against tumor necrosis factor (TNF)-? induced inflammatory stress by enhancing O-GlcNAcylation and inhibiting TNF-? induced phosphorylation of NF?B p65, thus inhibiting NF?B signaling.Quiescent rat aortic SMCs were pretreated with GlcN (5 mM), PUGNAc (10(-4) M) or vehicle and then stimulated with TNF-? (10 ng/ml). Both treatments inhibited TNF-?-induced expression of chemokines [cytokine-induced neutrophil chemoattractant (CINC)-2? and monocyte chemotactic protein (MCP)-1] and adhesion molecules [vascular cell adhesion molecule (VCAM)-1 and P-Selectin]. Both treatments inhibited TNF-? induced NF?B p65 activation and promoter activity, increased NF?B p65 O-GlcNAcylation and inhibited NF?B p65 phosphorylation at Serine 536, thus promoting I?B? binding to NF?B p65.There is a reciprocal relationship between O-GlcNAcylation and phosphorylation of NF?B p65, such that increased NF?B p65 O-GlcNAc modification inhibits TNF-?-Induced expression of inflammatory mediators through inhibition of NF?B 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.

SUBMITTER: Xing D

PROVIDER: S-EPMC3164132 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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O-GlcNAc modification of NFκB p65 inhibits TNF-α-induced inflammatory mediator expression in rat aortic smooth muscle cells.

Xing Dongqi D Gong Kaizheng K Feng Wenguang W Nozell Susan E SE Chen Yiu-Fai YF Chatham John C JC Oparil Suzanne S

PloS one 20110831 8

<h4>Background</h4>We 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 ...[more]

PMID: 21904602

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Project description:Rationale: Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular mortality and morbidity with increasing prevalence and incidence. The pathobiology of CAVD involves valvular fibrocalcification, and osteogenic and fibrogenic activities are elevated in aortic valve interstitial cells (VICs) from diseased valves. It has been demonstrated that activated NF-κB pathway was present in the early stage of CAVD process. There is currently no effective clinical drugs targeting NF-κB pathway for CAVD treatment. Therefore, it is of great clinical significance to seek effective treatments for valve calcification. Methods: In this study, we established immortal human valve interstitial cells (im-hVICs) with pGMLV-SV40T-puro lentivirus. Alizarin red staining and western blotting were performed to evaluate the calcification of immortal VICs supplemented with different compounds. The natural fusicoccane diterpenoid alterbrassicene A (ABA) was found to have potential therapeutic functions. Ribonucleic acid sequencing was used to identify the potential target of ABA. Platelet membrane-coated nanoparticle of ABA (PNP-ABA) was fabricated and the IBIDI pump was used to evaluate the adhesion ability of PNP-ABA. Murine wire-induced aortic valve stenosis model was conducted for in vivo study of PNP-ABA. Results: The natural fusicoccane diterpenoid ABA was found to significantly reduce the calcification of human VICs during osteogenic induction via inhibiting the phosphorylation P65. Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2 (BMP2) were down regulated with the treatment of ABA in human VICs. Additionally, molecular docking results revealed that ABA bound to RelA (P65) protein. Phosphorylation of P65 (Ser536) was alleviated by ABA treatment, as well as the nuclear translocation of P65 during osteogenic induction in human VICs. Alizarin red staining showed that ABA inhibited osteogenic differentiation of VICs in a dose-dependent manner. PNP-ABA attenuated aortic valve calcification in murine wire-induced aortic valve stenosis model in vivo. Conclusions: The establishment of im-hVICs provides a convenient cell line for the study of CAVD. Moreover, our current research highlights a novel natural compound, ABA, as a promising candidate to prevent the progression of CAVD.

Dataset Information

O-GlcNAc modification of NF?B p65 inhibits TNF-?-induced inflammatory mediator expression in rat aortic smooth muscle cells.

Publications

O-GlcNAc modification of NFκB p65 inhibits TNF-α-induced inflammatory mediator expression in rat aortic smooth muscle cells.

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