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-?B and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-?B activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-?B activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit I?B?. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-?B pathway and corresponding age-related inflammatory activation of endothelium.

SUBMITTER: Zinovkin RA 

PROVIDER: S-EPMC4169860 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other