Взаимодействие HIF1α с белками теплового шока HSP90 и HSP70 в коре головного мозга при гипоксии

Abstract

The aim of the study was to investigate the dynamics of expression of HIF1α, HSP90 and HSP70 in the cerebral cortex (CC) of rats with genetically determined differences in tolerance to oxygen shortage in hypobaric hypoxia of different severity, duration and multiplicity. Methods. The study was conducted on white mongrel male rats, divided into groups by sensitivity to acute hypobaric hypoxia (3% O₂, 190 mm Hg, 11.5 km). Hypobaric hypoxia (HBH) of different severity was modeled in a flow-type altitude chamber. The pressure in the chamber simulated “altitudes” of 3,000 m (14% O₂, 526 mm Hg), 5,000 m (10% O₂, 380 mm Hg), and 7,000 m (8% O₂, 290 mm Hg). Duration of a single exposure varied from 15 min to 4 h (15, 30, 45, 60 min, 2, and 4 h), and each exposure in an HBH course (daily sessions, 20 days) lasted for 60 min. Contents of HSP90 and HSP70 were measured in the CC cytoplasmic extract and content of HIF1α — in the CC nuclear extract using Western blotting. Results. The study showed for the first time that the baseline expression of HIF1α and HSP90 in normoxia was higher in CC of hypoxia low-resistance (LR) rats than in high-resistance rats, which indicated a high significance of HIF1α-HSP90-dependent mechanisms in maintaining CC oxygen homeostasis in LR rats under normal physiological conditions. In hypoxia of different severity and duration, the pattern of urgent expression of HSP90 and HIF1α changed from induction in mild (14% O₂, 526 mm Hg) and moderate (10% O₂, 380 mm Hg) hypoxia to suppression in severe hypoxia (8% O₂, 290 mm Hg). During the course of repeated, non-damaging hypoxia (10% O₂/14% O₂, 60 min, 20 days), a progressive increase in the content of HIF1α was associated with depressed expression of HSP90 and HSP70, which suggested a possible negative regulation by HIF1. Studying changes in HIF1α, HSP90 and HSP70 expression during single and repeated exposures to non-damaging hypoxia suggested that short courses (3—8 days) of moderate 60-min hypoxic exposures could be used to induce HIF1α-HSP90-dependent adaptive mechanisms. Repeated severe hypoxia caused a steady suppression of HSP90, HSP70 and HIF1α expression and failure of HIF1α-HSP90-dependent mechanisms of adaptation to oxygen deficiency. Conclusion. Using different modes of hypobaric hypoxia is a potential approach to modulation of HIF1α-HSP90 complex stability and effectiveness of HIF1-dependent mechanisms of adaptation to oxygen deficiency.