Preotective Effects Of Metabolic Related Hormones On Vascular Endothelial Cell Injury Induced By High Glucose/High Lipid

BackgroundVascular endothelial cell dysfunction is an early stage of pathological changes in diabetic vascular disease.Vascular endothelial dysfunction and metabolic disorders are closely related.The body's glycolipid metabolism is mainly regulated by metabolic-related hormones,metabolic-related hormones through the regulation of glycolipid metabolism,reduce high-sugar and high-fat on cardiovascular damage indirectly.GLP-1 and ghrelin are common appetite-regulating hormones.Both of them display multiple physiological functions beyond metabolic regulation.However,the effect of GLP-1 and ghrelin on endothelial biology is not fully understood.Diabetes-induced vascular complications are the major causes of morbidity and mortality in diabetic patients.Hyperglycemia is a key factor for the pathogenesis of vascular injury in diabetes.Hyperglycemia induces vascular damage probably through overproduction of ROS(reactive oxygen species,ROS).Fam3A(the family with sequence similarity 3A,Fam3A)is mainly localized in microvascular cells.However,its biological function remains largely unknown in hyperglycemia induces vascular damage.MethodIn the first part,HAMECs were exposed to HG/HL condition with GLP-1 or ghrelin treatment for exploring its influence and mechanism on HAMECs injury.In the other part,we investigate its role in high glucose-induced damage in HUVECs.Tthrough Knocking down the gene expression of Fam3A with siRNA or not,measuring the production of ROS,ATP synthesis and mitochondrial OCR in HUVECs treated by high glucose or not,the study verifies whether Fam3A has protective effect on oxidative damage and further detects the possible signaling pathways.ResultOur result showed that both GLP-1 and ghrelin decreased the number of TUNEL positive cells,and inhibited cleavage of caspase-3 and PARP,and ROS formation in HG/HL-exposed HMECs.Not ghrelin,but GLP-1 decreased the number of ?-Galactosidase positive cells.Furthermore,GLP-1 and ghrelin inhibited ERK1/2,JNK1/2,and p38 signaling,and inhibitors for JNK1/2 and p38 decreased the number of TUNEL positive cells.Moreover,GLP-1 suppressed Akt signaling and Akt inhibitor decreased the number of?-Galactosidase positive cell.However,ghrelin showed no effect on Akt signaling.High glucose increases the expression of Fam3A in HUVECs.Knocking down the gene expression of Fam3A exacerbates high glucose-induced increasing production of intracellular ROS and decreasing the ATP production and mitochondrial OCR.This process may be associated with the p38 MAPK signaling pathway.ConclusionTaken together,these results demonstrate that GLP-1 and ghrelin suppress HG/HL-induced endothelial apoptosis via inhibition of JNK1/2 and p38 signaling and GLP-1 alleviate endothelial senescence via inactivation of Akt signaling.Our study suggests that Fam3 A has protective effects against high glucose-induced oxidative damage.