Protective Effect Of Histone Deacetylase Inhibitor SAHA On Vascular Damage In Hypertensive Mice Induced By Intermittent Hypoxia

Background:Obstructive sleep apnea（OSA）refers to the people sleep at night when parts of pharyngeal collapse cause breathing difficulties and insufficient ventilation,accompanied by a variety of clinical symptoms,including hypoxemia,snoring,and the sharp fluctuations in intrathoracic negative pressure and so on,can cause a variety of organs and systems of injury,is a serious threat to the health of disease,more and more people with OSA and can not get effective detection and treatment,this leads to a pressing need to understand the mechanism and treatment of OSA.Objectives:This project from intermittent hypoxia（IH）cause endothelial dysfunction is a critical problem to obtain,under the condition of IH training mice model,applied physiology pharmacology and molecular biology,and other research methods,from the overall comprehensive team protein and molecular level to acetylation enzyme inhibitors in improving vascular endothelial dysfunction caused by IH the role and mechanism of,for the treatment of intermittent hypoxia caused by cardiovascular disease treatment of new ideas.Methods:A total of 32 male C57 mice were randomly divided into 4 groups:control group,control group,model group,model group,model group,8 mice in each group.Mice in model group were placed in a hypoxic chamber for 8 hours a day for 4 weeks,while mice in control group were not placed in a hypoxic chamber for normal feeding.We measured caudal artery systolic pressure（SBP）weekly in male mice with noninvasive caudal cuff method.From the 3rd week,mice in the administration group were intraperitoneally injected with SAHA(50 mg·kg^-1·day^-1)for 1 week,and the same solvent was injected intraperitoneally in the control group and the model group.The pathological changes of thoracic aorta were observed by hematoxylin-eosin（HE）and Masson staining.In order to evaluate the effect of intermittent hypoxia on the systolic function of thoracic aorta in mice,the diastolic function of thoracic aorta in mice was observed by X-ray vascular tension assay in vitro.Nitric oxide（NO）content in thoracic aorta was determined by colorimetric method.The content of ROS in thoracic aorta was detected by DHE fluorescence staining.Western blot（WB）was used to detect the expression of total e NOS、NOX4 and SOD in thoracic aorta.Results:The statistical results showed that after 4 weeks of modeling,compared with the control group,the SBP of the model group was significantly increased（P<0.01）;compared with the model group,the SBP of the SAHA treatment group was significantly decreased（P<0.05）.The results of in vitro vascular tension showed that IH would damage the endothelium-dependent relaxation function of the thoracic aorta in mice,but had no effect on the endothelium-independent relaxation function of the thoracic aorta.SAHA administration treatment would alleviate this damage（P<0.05）).The results of pathological staining showed that there was significant cardiovascular remodeling in the model group after 4 weeks of modeling,and SAHA could partially reverse cardiovascular remodeling（P<0.01）.The colorimetric results showed that compared with the model group,SAHA could up-regulate the NO content in the thoracic aorta（P<0.05）.DHE fluorescence staining results showed that compared with the model group,SAHA can down-regulate the content of ROS in the thoracic aorta of the model group（P<0.01）.WB results showed that SAHA reduced the content of ROS in the mouse thoracic aorta by up-regulating the content of SOD and e NOS,thereby reversing the damage of the mouse thoracic aorta（P<0.01）;down-regulating the content of NOX4 to reduce the amount of ROS in mice Oxidative stress response（P<0.05）.Conclusion:The protective effect of SAHA on the cardiovascular system during IH can improve the hypertension caused by IH by protecting the vascular endothelial function.