Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses
Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses
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DOI：
10.1007/s00540-017-2417-0
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发表时间：
2017-12-01
影响因子：
2.8
通讯作者：
Yamakage, Michiaki
中科院分区：
文献类型：
--
作者：
Kawaguchi, Ryoichi;Hirata, Naoyuki;Yamakage, Michiaki
脓毒症引起的心肌功能障碍的具体治疗策略仍有待确定。亚硝酸盐可能对败血症引起的心肌功能障碍具有心脏保护作用。本研究探讨了亚硝酸盐对严重脓毒症大鼠心肌功能、线粒体生物能量学的保护作用及其潜在的分子机制。采用盲肠结扎穿刺法（CLP）诱导雄性Wistar大鼠脓毒症。CLP后皮下注射生理盐水（NS组）或亚硝酸盐（亚硝酸盐组）。我们给亚硝酸盐不同剂量（0.1- 10mg /kg）以确定最有效剂量，并在CLP后8小时的离体心脏实验中检测心功能。我们在体外研究了亚硝酸盐管理的线粒体生物能量学和分子机制。在离体心脏实验中，中等亚硝酸盐剂量（1.0 mg/kg）组左心室发育压（96 +/- 5 mmHg）显著高于NS组（75 +/- 4 mmHg, P < 0.05）。亚硝酸盐组线粒体氧化磷酸化水平极显著高于NS组（P < 0.01）。免疫印迹显示，与NS组相比，亚硝酸盐显著提高了Akt的磷酸化水平（P < 0.05），降低了nf - κ B的核易位（P < 0.05）。亚硝酸盐也能提高严重脓毒症大鼠的存活率（P < 0.001）。我们的研究结果表明，中等剂量的亚硝酸盐通过调节应激信号反应，在器官、细胞和分子水平上改善脓毒性心肌功能障碍，从而提高生存率。
A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats.Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1-10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro.In isolated heart experiments, the left ventricular developed pressure (96 +/- 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 +/- 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-kappa B (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001).Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.