title: Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model.
abstract: Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 μmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during sepsis.
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical center, Dallas, Texas 75390-9160, USA. qun.zang@utsouthwestern.edu
authors.forename: Qun S
authors.initials: QS
authors.lastname: Zang
authors.forename: Hesham
authors.initials: H
authors.lastname: Sadek
authors.forename: David L
authors.initials: DL
authors.lastname: Maass
authors.forename: Bobbie
authors.initials: B
authors.lastname: Martinez
authors.forename: Lisha
authors.initials: L
authors.lastname: Ma
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kilgore
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Doug E
authors.initials: DE
authors.lastname: Frantz
authors.forename: Jane G
authors.initials: JG
authors.lastname: Wigginton
authors.forename: Fiemu E
authors.initials: FE
authors.lastname: Nwariaku
authors.forename: Steven E
authors.initials: SE
authors.lastname: Wolf
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Minei
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D018410:Pneumonia, Bacterial / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000150:complications*; D013296:Streptococcus pneumoniae; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D017382:Reactive Oxygen Species; D014810:Vitamin E; D006861:Hydrogen Peroxide