The Effect Of Ang(1-7)/MAS Pathway On Pancreatic Islet Microcirculation And Function In Rat With Long-term High-fat Diet

ObjectiveThough the intervention of Ang (1-7) and the MAS receptor antagonist A-779 on long-term high-fat diet induced insulin resistant rats, we observed the effects of Ang(1-7)/MAS pathway on pancreatic islet endothelial cells, islet microcirculation and islet function, and explored its regulation on long-term high fat diet inducedβ-cell dysfunction and the associated mechanism.Methods80 Wistar male rats were fed with basal diet for 2 weeks , 20 of which were randomly selected as normal control group (NC group, n = 20), given normal diet. The remaining were fed with high-fat diet, randomly divided into high-fat group (H0, n = 20), Ang (1-7) intervention group (H1 group, n = 20), Ang (1-7) + A-779 intervention group (H2 group, n = 20) after 12 weeks, then each of them were treated with saline, Ang (1-7), Ang (1-7) + A-779 though subcutaneous injection for 4 weeks. The intervention dose of Ang (1-7) and A-779 were both 300μg·kg^-1·d^-1. Colored microspheres technique (sedimentation method) was used to estimate the pancreatic microcirculation blood flow; immunofluorescence method was used to estimate vWF (von Willebrand factor) expression in islet and insulin relative concentration(IRC) in isletβ-cell ; RT-PCR was used to estimate the mRNA expression of vWF (vascular von Willebrand factor),a kind of islet endothelial cell markers; Intravenous glucose tolerance test (IVGTT) and intravenous insulin release test (IVIRT) were carried to estimateβ-cell functionResultsCompared with NC group, the glucose infusion rate (GIR) of H0 group decreased by 32% [(5.19±0.81 vs 7.65±0.45) mg·kg^-1·min^-1, P <0.05], the peak of insulin secretion was delayed, acute insulin response (AIR) decreased by 54% (42.25±14.39 vs 91.45±15.35, P <0.05), the expression of insulin in islet decreased significantly(P<0.05), pancreatic microcirculation blood flow decreased by 8.7% [(0.595±0.062 vs 0.652±0.089) ml·g^-1·min^-1, p <0.05], immunofluorescence staining showed vWF expression in islet decreased by 35% (relative concentrations were 13.8±2.21 vs 21.2±1.71 P <0.05), indicating the microvessel density increased significantly; The mRNA of vWF expression levels in islet decreased by 23% (P < 0.05)Given Ang (1-7) intervention, compared with the H0 group, the glucose infusion rate (GIR) of H1 group increased by 29% [(6.72±0.39 vs 5.19±0.81) mg·kg^-1·min^-1, P <0.05], with peak time of insulin secretion curve forward, acute insulin response (AIR) increased by 55% (65.65±17.52 vs 42.25±14.39, P <0.05), the expression of insulin in islet increased significantly(P<0.05),pancreatic microcirculation blood flow increased by 46% [(0.866±0.110 vs 0.595±0.062) ml·g^-1·min^-1, P <0.05], immunofluorescence staining showed vWF in islet expression decreased by 40% (relative concentrations were 19.3±3.16 vs 13.8±2.21 P <0.05),indicating the microvessel density increased significantly elevated; The mRNA expression levels of vWF in islet decreased by 23% (P<0.05);Given MAS receptor antagonist intervention at the same time, compared with the H1 group, the glucose infusion rate (GIR) of H2 group decreased by 21% [(5.33±0.31 vs 6.72±0.39) mg·kg^-1·min^-1, P<0.05], the peak of insulin secretion was delayed, acute insulin response (AIR) decreased by 24% (50.60±14.39 vs 65.65±17.52, P<0.05), the expression of insulin in islet decreased significantly ( P < 0.05), pancreatic microcirculation blood flow decreased by 35% [(0.561±0.099 vs 0.866±0.110) ml·g^-1·min^-1, P <0.05], immunofluorescence staining showed the expression of vWF in islet decreased by 25% (relative concentrations were 14.4±2.85 vs 19.3±3.16 P <0.05), The mRNA expression of vWF in islets decreased by 15% ( P <0.05).ConclusionIn long-term high fat diet induced insulin resistance rats, pancreatic microcirculation blood flow decreased slightly, islet microcirculation has emerged decompensation performance:endothelial cell dysfunction, decreased microvessel density. Through binding to its receptor MAS,Ang (1-7) improve endothelial function and islet microcirculation, thereby improving the islet function in rat with long-term high fat diet.