Elisabed Kvergelidze*,**, Tamar Barbakadze*,**, David Mikeladze*,**,§
* Faculty of Natural Sciences and Medicine, Ilia State University, 3/5 K. Cholokashvili Ave., 0162, Tbilisi, Georgia; ** Department of Biochemistry, IvaneBeritashvili Center of Experimental Biomedicine, 14 Gotua Str., 0160, Tbilisi, Georgia; §Academy Member, Georgian National Academy of Sciences
Abstract
There is growing evidence that the Rac1-activated NADPH oxidase system stimulates ROS production, increases the BDNF expression, and regulates neurogenesis. Thus, moderate ROS amount could have beneficial effects on signaling and neurogenesis. Thyroid hormones (TH), are involved in mechanisms of neuronal plasticity and function of glial cells after ischemic stroke. Our previous findings suggest that T3 regulates the neuronal actin cytoskeleton dynamics via αvβ3-integrin, which increases neuronal cell viability through the Rac1/NADPH oxidase pathway during hypoxia. We hypothesized that TH via αvβ3-integrin could regulate NADPH oxidase activity through Rac1/NOX2 interactions, or NOX4 expression, and consequently stimulate BDNF production. We analyzed the T3 and T4 effects on Rac1 binding to NOX2 in differentiated PC-12 cells and revealed, that T3 causes increases of the Rac1/NOX2 interaction, and this effect was significantly elevated after blocking of αvβ3 integrin by anti- αvβ3integrin antibodies in hypoxia. In contrast to NOX2, αvβ3-integrin inhibitory antibody significantly decreased NOX4 expression in differentiated PC-12 cells and abolished the T3-induced elevation of the BDNF secretion during hypoxia. Our findings suggest that T3 regulates the moderate activity of NOX2 via αvβ3-integrin-mediated Rac1 binding to NOX2, which stimulates the BDNF production and contributes to its neuroprotective signaling pathway activity during hypoxia.
Keywords:αvβ3-integrin; Rac1; NOX2; NOX4; hypoxia; PC-12