Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model.
Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model.
复制标题
DOI：
10.1371/journal.pone.0139416
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zang QS
中科院分区：
文献类型：
--
作者：
Yao X;Carlson D;Sun Y;Ma L;Wolf SE;Minei JP;Zang QS
我们先前已经证明，在肺炎相关脓毒症模型中，靶向线粒体的维生素E（Mito-Vit-E），一种线粒体ROS特异性抗氧化剂，可改善心脏功能并减轻炎症。在这项研究中，我们采用相同的方法来破译脓毒症后mtROS依赖性心脏炎症的信号通路。Sprague道利大鼠腹腔注射S.肺炎。30分钟后给予Mito-Vit-E、维生素E或溶媒。在接种后24小时的心肌中，Mito-Vit-E，而不是维生素E，显着保护mtDNA的完整性和减少mtDNA损伤。Mito-Vit-E减轻脓毒症诱导的DNA修复酶（包括DNA聚合酶γ、AP核酸内切酶、8-氧代鸟嘌呤糖基化酶和尿嘧啶-DNA糖基化酶）的减少。Mito-Vit-E显著改善了线粒体的代谢和膜完整性，抑制了线粒体DNA向细胞质的渗漏，抑制了Toll样受体9（TLR 9）途径因子MYD 88和Toll的上调，并限制了Toll样受体9与其配体TFAM在脓毒症心脏中的相互作用。Mito-Vit-E还使NF-κB和半胱天冬酶1失活，减少基本炎性体组分ASC的表达，并减少炎性细胞因子IL-1β。在体外，Mito-Vit-E和TLR 9抑制剂OND-I均抑制LPS诱导的心肌细胞中MYD 88、cAMP、ASC、活性caspase 1和IL-1β的上调。由于游离的mtDNA从受损的线粒体中逃逸，作为一种DAMP通过TLR 9刺激炎症，这些数据共同表明脓毒症诱导的心脏炎症至少部分地通过mtDNA-TLR 9-binding介导。最后，Mito-Vit-E减少了心肌损伤标志物肌钙蛋白-I的循环，减少了细胞凋亡，并改善了脓毒症心脏的形态，表明靶向抗氧化剂是脓毒症的潜在心脏保护方法。
We have previously shown that mitochondria-targeted vitamin E (Mito-Vit-E), a mtROS specific antioxidant, improves cardiac performance and attenuates inflammation in a pneumonia-related sepsis model. In this study, we applied the same approaches to decipher the signaling pathway(s) of mtROS-dependent cardiac inflammation after sepsis. Sepsis was induced in Sprague Dawley rats by intratracheal injection of S. pneumoniae. Mito-Vit-E, vitamin E or vehicle was administered 30 minutes later. In myocardium 24 hours post-inoculation, Mito-Vit-E, but not vitamin E, significantly protected mtDNA integrity and decreased mtDNA damage. Mito-Vit-E alleviated sepsis-induced reduction in mitochondria-localized DNA repair enzymes including DNA polymerase γ, AP endonuclease, 8-oxoguanine glycosylase, and uracil-DNA glycosylase. Mito-Vit-E dramatically improved metabolism and membrane integrity in mitochondria, suppressed leakage of mtDNA into the cytoplasm, inhibited up-regulation of Toll-like receptor 9 (TLR9) pathway factors MYD88 and RAGE, and limited RAGE interaction with its ligand TFAM in septic hearts. Mito-Vit-E also deactivated NF-κB and caspase 1, reduced expression of the essential inflammasome component ASC, and decreased inflammatory cytokine IL–1β. In vitro, both Mito-Vit-E and TLR9 inhibitor OND-I suppressed LPS-induced up-regulation in MYD88, RAGE, ASC, active caspase 1, and IL–1β in cardiomyocytes. Since free mtDNA escaped from damaged mitochondria function as a type of DAMPs to stimulate inflammation through TLR9, these data together suggest that sepsis-induced cardiac inflammation is mediated, at least partially, through mtDNA-TLR9-RAGE. At last, Mito-Vit-E reduced the circulation of myocardial injury marker troponin-I, diminished apoptosis and amended morphology in septic hearts, suggesting that mitochondria-targeted antioxidants are a potential cardioprotective approach for sepsis.