The peripheral blood monocytes of atherosclerotic patients are pre-activated
and have some of the features of tissue macrophages. Their adhesion to the
endothelium is 1.5 times higher than that of monocytes from healthy subjects,
and they express a number of receptors and antigens typical of tissue
macrophages. Additionally, earlier we showed that the biosynthesis of
gangliosides, whose main function is the formation of membrane rafts, is
significantly activated in blood monocytes from atherosclerotic patients, as
well as during the in vitro differentiation of normal
monocytes into macrophages. In this study, we investigated the expression of
membrane rafts on various monocyte subsets from healthy subjects and
atherosclerotic patients. Based on flow cytometry results, the monocytes in the
examined atherosclerotic patients were found to differ from those in healthy
subjects by a twofold increase in the proportion of the intermediate subset
(CD14++/CD16+) and by enhancement in the expression of
the fractalkine receptor CX3CR1 on the intermediate and non-classical subsets
(CD14++/CD16+ and CD14+/CD16++)
(2.3 and 1.8 times, respectively). This suggests a pre-activated state of
monocytes in atherosclerotic patients. At the same time, the expression of the
membrane raft marker on the monocyte subsets was similar in both studied
groups. However, a study of the in vitro differentiation of
monocytes into macrophages showed that the membrane raft expression increased 2
times as early as on the 1st day of culturing and 3 times on the 7th day
compared to that in freshly isolated monocytes. Therefore, it is suggested that
monocytes in atherosclerosis accumulate gangliosides that are used to form
membrane rafts during the macrophage differentiation after the migration of
monocytes into the arterial intima.
The therapeutic effect of mitochondria-targeted antioxidant 10-(6´-plastoquinonyl)decyltriphenylphosphonium bromide (SkQ1) in experimental models of acute inflammation and wound repair has been shown earlier. It was suggested that the antiinflammatory activity of SkQ1 is related to its ability to suppress inflammatory activation of the vascular endothelium and neutrophil migration into tissues. Here, we demonstrated that SkQ1 inhibits activation of mast cells (MCs) followed by their degranulation and histamine release in vivo and in vitro. Intraperitoneal injections of SkQ1 in the mouse air-pouch model reduced the number of leukocytes in the air-pouch cavity and significantly decreased the histamine content in it, as well as suppressing MC degranulation in the air-pouch tissue. The direct effect of SkQ1 on MCs was studied in vitro in the rat basophilic leukemia RBL-2H3 cell line. SkQ1 inhibited induced degranulation of RBL-2H3 cells. These results suggest that mitochondrial reactive oxygen species are involved in the activation of MCs. It is known that MCs play a crucial role in regulation of vascular permeability by secreting histamine. Suppression of MC degranulation by SkQ1 might be a significant factor in the antiinflammatory activity of this mitochondria-targeted antioxidant.
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