Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia.
Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia.
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DOI：
10.1016/j.freeradbiomed.2008.11.007
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发表时间：
2009-03-01
影响因子：
7.4
通讯作者：
Piantadosi, Claude A.
中科院分区：
文献类型：
--
作者：
Reynolds, Crystal M.;Suliman, Hagir B.;Hollingsworth, John W.;Welty-Wolf, Karen E.;Carraway, Martha Sue;Piantadosi, Claude A.
线粒体生物发生保护代谢免受由脂多糖（LPS）或其他细菌产物激活先天免疫产生的线粒体功能障碍。本研究在小鼠心脏中验证了toll样受体-4 （TLR4）的激活假说，即toll样受体-4 （TLR4）可以诱导线粒体损伤的早期基因，也可以通过诱导一氧化氮合酶（NOS2）激活线粒体生物发生。通过实时RT-PCR、Western分析、免疫化学和肌球蛋白重链（MHC）同型异构体分析，比较了野生型（Wt） C57BL/6J、TLR4−/−和NOS2−/−小鼠在亚致死热致死大肠杆菌（HkEC）后心肌线粒体损伤和线粒体生物发生的情况。HkEC后，Wt小鼠心肌mtDNA明显减少，TLR4和NOS2基因及蛋白表达增强，并在72h内恢复正常。HkEC在TLR4−/−和NOS2−/−中产生的细胞因子应激比Wt小鼠少，NOS2−/−小鼠的mtDNA损伤与Wt相似，两种敲除菌株由于线粒体转录体功能障碍而无法恢复mtDNA拷贝数。Wt小鼠也表现出最大的β-MHC亚型转换，但NOS2−/−和TLR4−/−菌株的MHC恢复滞后。NOS2−/−小鼠也意外地揭示了TLR4表达对NOS2的共同依赖性。这些发现表明，TLR4诱导NOS2对革兰氏阴性刺激后线粒体生物发生和MHC表达的优化具有决定性作用。
Mitochondrial biogenesis protects metabolism from mitochondrial dysfunction produced by activation of innate immunity by lipopolysaccharide (LPS) or other bacterial products. Here we tested the hypothesis in mouse heart that activation of toll-like receptor-4 (TLR4), which induces early-phase genes that damage mitochondria, also activates mitochondrial biogenesis through induction of nitric oxide synthase (NOS2). We compared three strains of mice: wild type (Wt) C57BL/6J, TLR4−/−, and NOS2−/− for cardiac mitochondrial damage and mitochondrial biogenesis by real-time RT-PCR, Western analysis, immunochemistry, and isoform analysis of myosin heavy chain (MHC) after sub-lethal heat-killed E. coli (HkEC). After HkEC, Wt mice displayed significant myocardial mtDNA depletion along with enhanced TLR4 and NOS2 gene and protein expression that normalized in 72h. HkEC generated less cytokine stress in TLR4−/− and NOS2−/− than Wt mice, and NOS2−/− mice had mtDNA damage comparable to Wt, both knockout strains failed to restore mtDNA copy number because of mitochondrial transcriptosome dysfunction. Wt mice also showed the largest β-MHC isoform switch, but MHC recovery lagged in the NOS2−/− and TLR4−/− strains. The NOS2−/− mice also unexpectedly revealed the co-dependency of TLR4 expression on NOS2. These findings demonstrate the decisive participation of NOS2 induction by TLR4 in optimization of mitochondrial biogenesis and MHC expression after gram negative challenge.
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影响因子：
5.7
作者：
Abraham, WT;Gilbert, EM;Bristow, MR
通讯作者：
Bristow, MR
影响因子：
4
作者：
Leary, SC;Shoubridge, EA
通讯作者：
Shoubridge, EA
影响因子：
5
作者：
Stein, B;Frank, P;Thoenes, M
通讯作者：
Thoenes, M
DOI：
10.1016/0735-1097(96)00140-4
发表时间：
1996-08-01
影响因子：
24
作者：
Dhalla, AK;Hill, MF;Singal, PK
通讯作者：
Singal, PK
影响因子：
8.8
作者：
Garnacho-Montero, J;Garcia-Garmendia, JL;Ortiz-Leyba, C
通讯作者：
Ortiz-Leyba, C