NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1
NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1
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DOI：
10.1093/cvr/cvr230
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发表时间：
2011-11-01
影响因子：
10.8
通讯作者：
Beauloye, Christophe
中科院分区：
文献类型：
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作者：
Balteau, Magali;Tajeddine, Nicolas;Beauloye, Christophe
目的研究高糖(HG)刺激心肌细胞NADPH氧化酶产生ROS的作用，但其机制尚不清楚。方法和结果原代培养的成年大鼠心肌细胞暴露于HG浓度(HG，21 mM)中，并与正常血糖水平(Lg，5 mM)进行比较。汞暴露激活了rac1GTP，并诱导p47Phox移位到质膜，导致NADPH氧化酶(NOX2)激活，ROS产生增加，胰岛素抵抗，最终细胞死亡。LG和HG处理的细胞中O-连接N-乙酰氨基葡萄糖(O-GlcNAc)残基水平的比较没有发现任何显著差异。6-氨基烟酰胺抑制磷酸戊糖途径(PPP)可抑制HG诱导的ROS的产生，但不能阻止Rac-1的上调和导致NOX2活化的p47Phox易位。葡萄糖摄取的调节对HG诱导的氧化应激和毒性几乎没有影响。更有趣的是，非代谢葡萄糖类似物(即3-O-甲基-D-吡喃葡萄糖苷和α-甲基-D-吡喃葡萄糖苷)复制了HG的毒性作用。结论糖代谢增加本身并不触发NADPH氧化酶的激活，但PPP需要PPP为NOX2提供NADPH并产生ROS。NOX2的激活是葡萄糖通过SGLT1转运的结果，这表明细胞外的代谢信号转化为细胞内的离子信号。
Aims Exposure to high glucose (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase in cardiomyocytes, but the underlying mechanism remains elusive. In this study, we have dissected the link between glucose transport and metabolism and NADPH oxidase activation under hyperglycaemic conditions.Methods and results Primary cultures of adult rat cardiomyocytes were exposed to HG concentration (HG, 21 mM) and compared with the normal glucose level (LG, 5 mM). HG exposure activated Rac1GTP and induced p47phox translocation to the plasma membrane, resulting in NADPH oxidase (NOX2) activation, increased ROS production, insulin resistance, and eventually cell death. Comparison of the level of O-linked N-acetylglucosamine (O-GlcNAc) residues in LG-and HG-treated cells did not reveal any significant difference. Inhibition of the pentose phosphate pathway (PPP) by 6-aminonicotinamide counteracted ROS production in response to HG but did not prevent Rac-1 upregulation and p47phox translocation leading to NOX2 activation. Modulation of glucose uptake barely affected oxidative stress and toxicity induced by HG. More interestingly, non-metabolizable glucose analogues (i.e. 3-O-methyl-D-glucopyranoside and alpha-methyl-D-glucopyranoside) reproduced the toxic effect of HG. Inhibition of the sodium/glucose cotransporter SGLT1 by phlorizin counteracted HG-induced NOX2 activation and ROS production.Conclusion Increased glucose metabolism by itself does not trigger NADPH oxidase activation, although PPP is required to provide NOX2 with NADPH and to produce ROS. NOX2 activation results from glucose transport through SGLT1, suggesting that an extracellular metabolic signal transduces into an intracellular ionic signal.