MITOCHONDRIA-TARGETED ANTIOXIDANT SKQ1 REGULATES OF SIGNAL SYSTEM KEAP1/NRF2/ARE AND APOPTOSIS IN THE LEUKOCYTES OF BLOOD UNDER OXIDATIVE STRESS

Abstract

This study demonstrated that hyperoxia induced (0.5 MPa, 90 min) oxidative stress decreased mRNA level of Nrf2 transcription factor and Nrf2 induced genes encoding antioxidant enzymes (SOD1, CAT, GPx4) in leukocytes of rat blood. The change in gene expression profiles in hyperoxia was accompanied by disbalance of antioxidant enzyme activities in the leukocytes – activation of superoxide dismutase, and inhibition of catalase, glutathione peroxidase. The administration of SkQ1 (50 nmol/kg during 5 days) significantly increased mRNA level of Nrf2 transcription factor and Nrf2 induced genes encoding antioxidant enzymes SOD2 and GPx4 and nor malized the transcriptional activity of the SOD1 and CAT genes in the leukocytes under the hyperoxia induced oxidative stress. Catalase and glutathione peroxidase activity in the leukocytes increased concurrently with reversion of superoxide dismutase activity to the control level. The protective effect of SkQ1 in hyperoxia induced oxidative stress may be realized via direct antioxidant activity and the stimulation of the Keap1/Nrf2/ARE defense system. Administration of SkQ1 in extremely low amounts (50 nmol/kg for 5 days) effectively inhibits the accumulation of lipid peroxidation molecular products, normalizes the structural state of lymphocyte membranes and the level of their apoptosis under the condition of physiological standard and oxidative stress.