Regulatory Mechanism Of SENP1 On Neuroinflammation And Cognitive Dysfunction Of Mice Induced By Chronic Intermittent Hypoxia

Objective Chronic intermittent hypoxia(CIH),as the main pathophysiological feature of obstructive sleep apnea hypopnea syndrome(OSAHS),which can induce inflammation in central nervous system(CNS),and cause neuronal impairment or apoptosis,leading to cognitive insult,but the specific mechanism remains unclear.Small ubiquitin-related modifier materialized(SUMO)is a dynamic process of protein's post-translational modification form,which can be reversed by SUMO-specific proteases(SENPs).Some key proteins of inflammatory pathways have been identified to undergo SUMOylation.However,the role and molecular mechanism of SUMOylation in CIH-induced neuroinflammation are not fully understood.In previous CIH-induced inflammation of microglia study,we found that CIH significantly down-regulated the expression of SENP1,and SENP1 overexpression significantly inhibited CIH-induced inflammatory responses.In the present study,we aimed to conduct the following studies:? CIH induced neuroinflammatory response in vitro and in vivo,and cognitive dysfunction of mice;? The regulatory mechanism of SENP1 on CIH-induced neuroinflammation and neuronal apoptosis;? The effect mechanism of SENP1 on CIH-induced neuroinflammation and cognitive function of mice.Methods(1)Differentially expressed genes associated with hippocampal hypoxia injury and SUMOylation in mice was analyzed using bioinformatics analysis;(2)BV-2 microglial cells of SENP1 overexpression were constructed;(3)SENP1 knockdown mice were conducted;(4)Intermittent hypoxia device was used to create CIH cells and animal models.(5)The cognitive ability of mice was tested by Morris water maze test.(6)The expressions of SENP1,inflammatory factors,neuronal apoptosis-related protein markers were detected by molecular biology analysis.Results(1)Differentially expression genes heat maps and volcanic figure results showed that the expression of SENP1 in the hippocampus of mice with CIH treatment was significantly decreased compared with that in mice under normoxic condition;Quantitative real-time PCR(qRT-PCR),western blot analysis and immunohistochemical staining results showed that the expression of SENP1 in the hippocampus of mice with CIH treatment was significantly downregulated.(2)In vitro results showed that CIH induced inflammatory response in microglia and neuronal apoptosis;SENP1 overexpression significantly inhibited the inflammation and neuronal apoptosis induced by CIH;CIH induced the SUMOylation of NEMO,reduced the expression of NEMO;SENP1 overexpression significantly inhibited the SUMOylation of NEMO,and increased the expression of NEMO;After the overexpression of SENP1 in BV-2 cells,the siRNA of NEMO was applied to block the elevation of NEMO,and the inhibition of inflammatory response and neuronal apoptosis were found to be enhanced again;(3)In vivo results showed that CIH induced inflammatory response and neuronal apoptosis in the hippocampus of mice,and Morris water maze test results showed that the latency period of mice in the CIH group was significantly longer than that in the normoxia group,and the times of entering the platform area and the dwell time in the target quadrant were significantly decreased.SENP1 knockdown significantly enhanced CIH-induced inflammatory response and neuronal apoptosis,increased the latency period of mice in the CIH group,and decreased the times of entering the platform area and the dwell time in the target quadrant;CIH induced the SUMOylation of NEMO and downregulated the expression of NEMO;SENP1 depletion significantly promoted CIH-induced SUMOylation of NEMO and reduced the expression of NEMO.Conclusion SENP1 regulates NF-?B signaling pathways,neuroinflammation and neuronal apoptosis induced by CIH through mediating the SUMOylation of NEMO and the expression of NEMO,thus contributing to the change in cognitive ability of mice.