title: Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model.
abstract: 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.
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Carlson
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Lisha
authors.initials: L
authors.lastname: Ma
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Wolf
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Minei
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, United States of America.
authors.forename: Qun S
authors.initials: QS
authors.lastname: Zang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000032:analysis; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000633:toxicity; D018805:Sepsis / Q000209:etiology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D013481:Superoxides / Q000378:metabolism / Q000633:toxicity; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014336:Troponin / Q000032:analysis; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D051217:Toll-Like Receptor 9; D014336:Troponin; D013481:Superoxides; D014810:Vitamin E