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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/H515    most recent 01025.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Zou, L. Articles by Chatham, J. C. Search for Related Content PubMed PubMed Citation Articles by Zou, L. Articles by Chatham, J. C.

Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-B signaling

¹Department of Cell Biology, ²Department of Surgery and Center for Surgical Research, and ³Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 24 September 2008 ; accepted in final form 8 December 2008

We have previously demonstrated that in a rat model of trauma-hemorrhage (T-H), glucosamine administration during resuscitation improved cardiac function, reduced circulating levels of inflammatory cytokines, and increased tissue levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins. The mechanism(s) by which glucosamine mediated its protective effect were not determined; therefore, the goal of this study was to test the hypothesis that glucosamine treatment attenuated the activation of the nuclear factor-B (NF-B) signaling pathway in the heart via an increase in protein O-GlcNAc levels. Fasted male rats were subjected to T-H by bleeding to a mean arterial blood pressure of 40 mmHg for 90 min followed by resuscitation. Glucosamine treatment during resuscitation significantly attenuated the T-H-induced increase in cardiac levels of TNF- and IL-6 mRNA, IB- phosphorylation, NF-B, NF-B DNA binding activity, ICAM-1, and MPO activity. LPS (2 µg/ml) increased the levels of IB- phosphorylation, TNF-, ICAM-1, and NF-B in primary cultured cardiomyocytes, which was significantly attenuated by glucosamine treatment and overexpression of O-GlcNAc transferase; both interventions also significantly increased O-GlcNAc levels. In contrast, the transfection of neonatal rat ventricular myocytes with OGT small-interfering RNA decreased O-GlcNAc transferase and O-GlcNAc levels and enhanced the LPS-induced increase in IB- phosphorylation. Glucosamine treatment of macrophage cell line RAW 264.7 also increased O-GlcNAc levels and attenuated the LPS-induced activation of NF-B. These results demonstrate that the modulation of O-GlcNAc levels alters the response of cardiomyocytes to the activation of the NF-B pathway, which may contribute to the glucosamine-mediated improvement in cardiac function following hemorrhagic shock.

nuclear factor-B; cytokines; neonatal rat ventricular myocytes; O-linked N-acetylglucosamine

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