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.

Prospects for Drugs Based on the Mitochondria-Targeting Antioxidant SkQ1 in Treatment of Wounds with Impaired Healing

“…A statistically significant reduction in wound area compared to the control was detected on the 4th and 7th days. Histological analysis on the 14 th day of the experiment showed that in the wounds that were closed by this time, the animals receiving SkQ1 contained thicker bundles of collagen fibers than in the control that presumably caused by an increased activity of myofibroblasts [54].…”

“…Counting the number of neutrophils in the early stages of wound healing showed a more than twofold decrease in the number of neutrophils after 7 hours in SkQ1 treated rats. In the maturation phase of the granulation tissue, SkQ1 caused a 3-fold increase in the number of myofibroblasts expressing smooth-muscle beta-actin [54].…”

“…Подсчет количества нейтрофилов на ранних сроках заживления ран показал более чем двукратное уменьшение количества нейтрофилов через 7 час. В фазе созревания грануляционной ткани SkQ1 вызывал 3-х кратное увеличение коли-чества миофибробластов, экспрессирующих глад-комышечный бета-актин [54].…”

“…Статистически значимое умень-шение площади раны по сравнению с контролем было обнаружено на 4-ый и 7-ой дни. Гистологиче-ский анализ на 14-е сутки эксперимента показал, что в затянувшихся к этому времени ранах у животных, получавших SkQ1, содержатся более толстые пучки коллагеновых волокон, чем в конт-роле, что может быть связано с повышением актив-ности миофибробластов [54].…”

“…Действие SkQ1 было исследовано также в моделях острого асептического воспаления [54]. В первой модели воспаление индуцировали путем введения под кожу в межлопаточной области покровных стёкол.…”