title: Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium.
abstract: Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylphosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in ICAM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and corresponding age-related inflammatory activation of endothelium.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia. Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zinovkin
authors.affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Valeria P
authors.initials: VP
authors.lastname: Romaschenko
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Ivan I
authors.initials: II
authors.lastname: Galkin
authors.affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia. Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Vlada V
authors.initials: VV
authors.lastname: Zakharova
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia. Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Pletjushkina
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia. Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Chernyak
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia. Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Ekaterina N
authors.initials: EN
authors.lastname: Popova
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D000975:Antioxidants; C090509:Icam1 protein, mouse; D015850:Interleukin-6; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D010971:Plastoquinone