Reduction of cardiomyocyte S-nitrosylation by S-nitrosoglutathione reductase protects against sepsis-induced myocardial depression
Reduction of cardiomyocyte S-nitrosylation by S-nitrosoglutathione reductase protects against sepsis-induced myocardial depression
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DOI：
10.1152/ajpheart.00887.2012
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发表时间：
2013-04-01
影响因子：
4.8
通讯作者：
Ichinose, Fumito
中科院分区：
文献类型：
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作者：
Sips, Patrick Y.;Irie, Tomoya;Ichinose, Fumito
2005年10月27日，中国科学院院士。通过S-亚硝基谷胱甘肽还原酶减少心肌细胞S-亚硝基化可防止脓毒症诱导的心肌抑制。Am J Physiol Heart Circ Physiol 304：H1134-H1146，2013。首次发表于2013年2月15日; doi：10.1152/ajpheart.00887.2012.-心肌抑制是脓毒症患者发病率和死亡率的重要因素。一氧化氮（NO）在脓毒性心肌病的发展中起着重要作用，但也具有保护作用。最近的证据表明，NO通过蛋白质S-亚硝基化对心血管系统发挥其许多下游作用，S-亚硝基谷胱甘肽还原酶（GSNOR）是一种促进脱亚硝基化的酶，其负调控S-亚硝基谷胱甘肽还原酶（GSNOR）。我们验证了通过增加GSNOR活性减少心肌细胞S-亚硝基化可以改善脓毒症期间心肌功能障碍的假设。因此，我们产生了心肌细胞特异性过表达GSNOR的小鼠（GSNOR-CMTg小鼠），并使其遭受内毒素休克。体内和离体心脏功能的测量显示，与野生型（WT）小鼠相比，GSNOR-CMTg小鼠在脂多糖攻击（LPS，50 mg/kg）后具有显著改善的心脏功能。与WT细胞相比，从脓毒症GSNOR-CMTg小鼠分离的心肌细胞显示出相应的收缩性改善。然而，收缩期Ca 2+释放在LPS后两种基因型中类似地被抑制，表明GSNOR-CMTg心肌细胞在脓毒症期间具有增加的Ca 2+敏感性。两种基因型的LPS处理的心脏中炎症参数同样增加，并且在LPS攻击之前或之后在GSNOR过表达的心脏中没有发现NO合酶表达水平的代偿性变化。然而，GSNOR过表达显着减少总的心脏蛋白S-亚硝基化在脓毒症。总之，我们的研究结果表明，增加心肌细胞的去亚硝基化能力，防止脓毒症诱导的心肌抑制。我们的研究结果表明，在脓毒症期间特异性地减少蛋白S-亚硝基化通过增加心肌肌丝对Ca 2+的敏感性来改善心脏功能。
Sips PY, Irie T, Zou L, Shinozaki S, Sakai M, Shimizu N, Nguyen R, Stamler JS, Chao W, Kaneki M, Ichinose F. Reduction of cardiomyocyte S-nitrosylation by S-nitrosoglutathione reductase protects against sepsis-induced myocardial depression. Am J Physiol Heart Circ Physiol 304: H1134-H1146, 2013. First published February 15, 2013; doi: 10.1152/ajpheart.00887.2012.-Myocardial depression is an important contributor to morbidity and mortality in septic patients. Nitric oxide (NO) plays an important role in the development of septic cardiomyopathy, but also has protective effects. Recent evidence has indicated that NO exerts many of its downstream effects on the cardiovascular system via protein S-nitrosylation, which is negatively regulated by S-nitrosoglutathione reductase (GSNOR), an enzyme promoting denitrosylation. We tested the hypothesis that reducing cardiomyocyte S-nitrosylation by increasing GSNOR activity can improve myocardial dysfunction during sepsis. Therefore, we generated mice with a cardiomyocyte-specific overexpression of GSNOR (GSNOR-CMTg mice) and subjected them to endotoxic shock. Measurements of cardiac function in vivo and ex vivo showed that GSNOR-CMTg mice had a significantly improved cardiac function after lipopolysaccharide challenge (LPS, 50 mg/kg) compared with wild-type (WT) mice. Cardiomyocytes isolated from septic GSNOR-CMTg mice showed a corresponding improvement in contractility compared with WT cells. However, systolic Ca2+ release was similarly depressed in both genotypes after LPS, indicating that GSNOR-CMTg cardiomyocytes have increased Ca2+ sensitivity during sepsis. Parameters of inflammation were equally increased in LPS-treated hearts of both genotypes, and no compensatory changes in NO synthase expression levels were found in GSNOR-overexpressing hearts before or after LPS challenge. GSNOR overexpression however significantly reduced total cardiac protein S-nitrosylation during sepsis. Taken together, our results indicate that increasing the denitrosylation capacity of cardiomyocytes protects against sepsis-induced myocardial depression. Our findings suggest that specifically reducing protein S-nitrosylation during sepsis improves cardiac function by increasing cardiac myofilament sensitivity to Ca2+.