Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-κB signaling
Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-κB signaling
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DOI：
10.1152/ajpheart.01025.2008
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发表时间：
2009-02-01
影响因子：
4.8
通讯作者：
Chatham, John C.
中科院分区：
文献类型：
--
作者：
Zou, Luyun;Yang, Shaolong;Chatham, John C.
Zou L，Yang S，Champattanachai V，Hu S，Chaudry IH，Marchase RB，Chatham JC。葡萄糖胺通过增加蛋白质 O-GlcNA 酰化和减弱 NF-κ B 信号传导来改善创伤出血后的心脏功能。 Am J Physiol Heart Circ Physiol 296：H515-H523，2009。首次发表于 2008 年 12 月 19 日； doi: 10.1152/ajpheart.01025.2008.-我们之前已经证明，在创伤出血 (T-H) 的大鼠模型中，复苏期间给予葡萄糖胺可以改善心脏功能，降低炎症细胞因子的循环水平，并增加蛋白质上 O-连接的 N-乙酰葡萄糖胺 (O-GlcNAc) 的组织水平。氨基葡萄糖介导其保护作用的机制尚未确定；因此，本研究的目的是检验以下假设：氨基葡萄糖治疗通过增加蛋白质 O-GlcNAc 水平来减弱心脏中核因子 -kappa B (NF-kappa B) 信号通路的激活。禁食的雄性大鼠通过放血至平均动脉血压 40 mmHg 90 分钟，然后进行复苏来进行 T-H。复苏期间的葡萄糖胺治疗显着减弱了 T-H 诱导的 TNF-α 和 IL-6 mRNA、I kappa B-α 磷酸化、NF-kappa B、NF-kappa B DNA 结合活性、ICAM-1 和 MPO 活性心脏水平的增加。 LPS（2μg/ml）增加了原代培养的心肌细胞中IκB-α磷酸化、TNF-α、ICAM-1和NF-κB的水平，而葡萄糖胺处理和O-GlcNAc转移酶的过表达显着减弱了这种水平；这两种干预措施也显着提高了 O-GlcNAc 水平。相反，用 OGT 小干扰 RNA 转染新生大鼠心室肌细胞可降低 O-GlcNAc 转移酶和 O-GlcNAc 水平，并增强 LPS 诱导的 I kappa B-α 磷酸化增加。巨噬细胞系 RAW 264.7 的葡萄糖胺处理也增加了 O-GlcNAc 水平，并减弱了 LPS 诱导的 NF-κ B 激活。这些结果表明，O-GlcNAc 水平的调节改变了心肌细胞对 NF-κ B 途径激活的反应，这可能有助于葡萄糖胺介导的失血性休克后心脏功能的改善。
Zou L, Yang S, Champattanachai V, Hu S, Chaudry IH, Marchase RB, Chatham JC. Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-kappa B signaling. Am J Physiol Heart Circ Physiol 296: H515-H523, 2009. First published December 19, 2008; doi: 10.1152/ajpheart.01025.2008.-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-kappa B (NF-kappa 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-alpha and IL-6 mRNA, I kappa B-alpha phosphorylation, NF-kappa B, NF-kappa B DNA binding activity, ICAM-1, and MPO activity. LPS ( 2 mu g/ml) increased the levels of I kappa B-alpha phosphorylation, TNF-alpha, ICAM-1, and NF-kappa 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 I kappa B-alpha phosphorylation. Glucosamine treatment of macrophage cell line RAW 264.7 also increased O-GlcNAc levels and attenuated the LPS-induced activation of NF-kappa B. These results demonstrate that the modulation of O-GlcNAc levels alters the response of cardiomyocytes to the activation of the NF-kappa B pathway, which may contribute to the glucosamine-mediated improvement in cardiac function following hemorrhagic shock.