关键词: 慢性间歇性低氧, 胸主动脉, 小泛素样修饰特异性蛋白酶1, 低氧诱导因子1α, 血管内皮损伤

Abstract:

Objective To discuss the effect of the small ubiquitin-like modifier-specific protease 1 （SENP-1）/hypoxia-inducible factor 1α （HIF-1α） pathway on chronic intermittent hypoxia （CIH）-induced vascular endothelial injury in the rats， and to clarify the related mechanism. Methods The SD rats were randomly divided into control group and CIH group， and then the rats in each group were further divided into 2， 4， and 6-week subgroups， and there were 8 rats in each subgroup. The rats in CIH group were exposed to CIH in a CIH chamber to induce CIH and create the obstructive sleep apnea hypopnea syndrome （OSAHS） models， while the rats in control group were exposed to normoxic conditions.The serum and thoracic aorta tissue of the rats in various groups were collected at each time point. HE staining was used to observe the thoracic aorta vascular injury of the rats in various groups； ELISA method was used to detect the levels of nitric oxide （NO）， endothelin-1 （ET-1）， von Willebrand factor （vWF）， and thrombomodulin （TM） in serum of the rats in various groups； Western blotting method was used to detect the expression levels of SENP-1， HIF-1α， and vascular endothelial growth factor A （VEGFA） proteins in thoracic aorta tissue of the rats in various groups.In vitro， the aortic endothelial cells （rAECs） of the rats were cultured and infected with SENP-1 shRNA adenovirus （sh-SENP-1） to construct the cell line with low expression of SENP-1. The CIH was used to induce the vascular endothelial cell injury， and the cells were divided into CIH group， CIH+sh-NC group， and CIH+sh-SENP-1 group； control group was set up separately. CCK-8 method was used to detect the proliferation activities of the cells in various groups； ELISA method was used to detect the activities of lactate dehydrogenase （LDH） in the supernatant and the levels of NO， ET-1， malondialdehyde （MDA）， and activities of superoxide dismutase （SOD） in the cells in various groups； flow cytometry was used to detect the apoptotic rates of the cells in various groups； Western blotting method was used to detect the expression levels of SENP-1， HIF-1α， and VEGFA proteins in the cells in various groups. Results With the extension of CIH induction time， compared with control group， the thoracic aorta endothelium in CIH group gradually became rough and significantly thickened， the level of serum NO of the rats in CIH group was decreased （P<0.05）， and the levels of serum ET-1， vWF， and TM， and the expression levels of SENP-1， HIF-1α， and VEGFA proteins in thoracic aorta tissue were increased （P<0.05）. Compared with control group， the proliferation activity of the cells in CIH group was decreased （P<0.05）， the LDH activity in the supernatant， the levels of ET-1， MDA， and the apoptotic rate in the cells were increased （P<0.05）， while the levels of NO and activity of SOD in the cells were decreased （P<0.05）， and the expression levels of SENP-1， HIF-1α， and VEGFA proteins in the cells were increased （P<0.05）. Compared with CIH group， the proliferation activity of cells in CIH+sh-SENP-1 group was increased （P<0.05）， the activity of LDH in the supernatant， the levels of ET-1， MDA， and the apoptotic rate of the cells were decreased （P<0.05）， while the level of NO and activity of SOD in the cells were increased （P<0.05）， and the expression levels of SENP-1， HIF-1α， and VEGFA proteins were decreased （P<0.05）. Conclusion The SENP-1/HIF-1α pathway is highly activated in the thoracic aorta injury tissue of the rats induced by CIH. Silencing SENP-1 expression can reduce CIH-induced vascular endothelial cell injury， and its mechanism may be related to downregulating the activation level of SENP-1/HIF-1α pathway.

Key words: Chronic intermittent hypoxia, Thoracic aorta, Small ubiquitin-like modified specific protease 1, Hypoxic inducible factor 1α, Vascular endothelial injury