期刊
AGING-US
卷 6, 期 8, 页码 661-674出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100685
关键词
mitochondrial reactive oxygen species; endothelium; TNF; NF-kappa B; cell adhesion molecules
资金
- Russian Foundation for Basic Research [12-04-00538, 12-04-01563, 13-04-40309, 14-04-31680]
- Russian Scientific Foundation [14-14-00055]
- Russian Science Foundation [14-14-00055] Funding Source: Russian Science Foundation
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-kappa B and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-kappa B activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-kappa B activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit I kappa B alpha. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-kappa B pathway and corresponding age-related inflammatory activation of endothelium.
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