HIF-1α Signal Pathway Related To Diabetes Brain Microvascular Disease And Intervention Research

Objective: This research through to investigate the effect of Gastricbypass surgery(DJB) surgery on type2diabetic SD rats and normal mice,observe preoperative and postoperative metabolic indicators changedynamically, and the expression of HIF-1α,MMP-9and Claudin-5in ratsmicrovascular endothelial cells postoperative8weeks,evans blue dyeingdetect BBB permeability,preliminary discussion the microvascular injurymechanisms of T2DM rat and DJB effects on DM brain microvascularcomplications and BBB.Methods:(1)808-weeks-age male SD rats, were randomly divided intohigh-fat diet group (n=40), normal food diet group (n=40), respectivelyfeed with high fat diet and normal diet.(2) Streptozotocin (STZ)(30mg/kg)by intraperitoneal was injected to establish the model of T2DM rats after fedhigh-fat diet8weeks. type2diabetic rats and normal SD rats wererandomized divided into four groups:type2diabetes-operation group(DROgroup),type2diabetes-sham operation group(DSO group), normal-operationgroup（NRO group），normal-sham operation group（NSO group）. Theweight、FBG、FINS、TG and TC of rats in each group were detected inpreoperative,4weeks and8weeks after surgery. The rats were killed aftersurgery8weeks.The protein level of HIF-1α,MMP-9and Claudin-5in thebrain microvascular endothelial cells were determined with Western blottingand immunohistochemistry staining.Results: The total of diabetes mold were31, modeling success rate was77.5%(31/40), postoperative DJB the rats survival rate is as follows:DRO:75%(9/12), DSO:83%(10/12), NRO:83%(10/12), NSO:91.7%(11/12).①DRO groups weight decreased from preoperative401.30±66.827gto337.80±71.731g, compare with other groups at the same point of time, thedifference was statistically significant (P <0.05)8weeks after surgery;②TheDRO group fasting blood glucose (FBG) declined from preoperative23.580±4.2679mmol/L to9.500±1.3728mmol/L, which significantly lower than thethe DSO group (P <0.05) after surgery8weeks, the DSO group, NRO group,NSO group FBG had no significant change (P>0.05) before and after surgery;③DRO group TC declined from preoperative0320±0.3650mmol/L to1.4440±0.3742mmol/L, TG decline from preoperative2.6790±1.0876mmol/L to0.7960±0.3889mmol/L,which significantly lower than thecorresponding time points DSO group’s (P <0.05);④The DRO grouppostoperative8weeks fasting insulin from preoperative21.73±1.19mIU/Ldropped to16.65±0.542mIU/L(P<0.05), and significantly lower than the theDSO group (P <0.05).Immunohistochemical staining: DM group rat cortical microvascularendothelial cells, HIF-1α was strongly positive staining expression mainly inthe cytoplasm, the nucleus, and the DSO group staining stronger than theDRO group’s（P＜0.05）after surgery8weeks, DM group rat corticalmicrovascular endothelial cells the expression of claudin-5was weaklypositive, DRO staining stronger than the DSO group’（sP＜0.05）.NRO group,the NSO group of rats claudin-5expression was strong positive, which had nosignificant difference in the4group rat cortical microvascular endothelialcells MMP-9staining. Western blot: DM rats HIF-1a protein expression is higher than that ofthe NRO and NSO group, claudin-5is lower than the NRO and group,hippocampal cortex claudin-5level of the NSO and DRO group8weeks aftersurgery is higher than the DSO group’s (P <0.05), HIF-1a level less than theDSO group’s (P <0.05), the expression of MMP-9level was no significantdifference in all groups (P>0.05).DM (DRO/DSO) EB content compared with normal control group(NRO/NSO) were significantly higher (P <0.05), the DRO group EB contentwas decreased than DSO group (P <0.05)8weeks after surgery.Conclusion:1after gastric bypass，type2diabetes fasting blood glucose, blood lipidssignificantly reduced, insulin resistance improved, to prove the efficacy ofrats with type2diabetes, prove the efficacy of the surgery.2Hyperglycemia through increase HIF-1alpha protein expression todecrease expression of tight junction Claudin-5protein level, leading tomicrovascular disease and increase the permeability of the BBB.3Type2diabetic rat after gastric bypass HIF-1α expression declined onbrain vascular endothelial cell and BBB permeability improved,maybethrough the regulation of HIF-1α’downstream signaling molecules to reduceT2DM rats cerebrovascular disease;MMP-9expression in the four groups ofrats have no significant difference, and may be related to modeling time andlow expression level of MMP-9expression in brain microvascular.