Correlation Between Diabetic Cardiomyopathy And CGAS-STING Pathway In OVE26 Type 1 Diabetic Mice

Background:During the last decade,there has been ample research into the mechanisms and financial characteristics of diabetic cardiomyopathy,while effective methods to prepare for and cure such disease have remained quite modest.Diabetic cardiomyopathy,owing to diabetes-induced dysregulation in associated glucose and lipid metabolism,contributes to increased oxidative stress and subsequent activate multiple inflammatory pathways which mediate intra-and extracellular damage,creating pathological cardiac remodeling,as well as dysfunction of the myocardial function.Research on the cyclic guanosine monophosphate-adenosine phosphate(cGAMP)synthase-interferon gene stimulator pathway(cGAS-STING pathway)has emerged as a hot topic recently.Initially,investigations of the cGAS-STING pathway were restricted to the context of infectious diseases.However,as the research gradually progressed,some work demonstrated that the cGAS-STING pathway could affect metabolic disorders and thus cause metabolic-related diseases.Hence,studies on whether changes in cGAS-STING pathway expression exert an impact in the disease progression of diabetic cardiomyopathy would be warranted.In the present study,the role of the cGAS-STING pathway in diabetic cardiomyopathy was initially observed by constructing a type 1 diabetes mellitus(T1DM)diabetic cardiomyopathy model in OVE26 mice and a high-glucose environment in rat cardiomyocytes.Objectives:1.Whether the cGAS-STING pathway functions in disease progression in a mouse model of type one diabetes-induced diabetic cardiomyopathy.2.A brief look at whether the cGAS-STING pathway is involved in the progression of type one diabetes-induced diabetic cardiomyopathy at different time points.3.Whether stimulation of STING expression affects an effect of the cGAS-STING pathway in a cellular model of diabetic cardiomyopathy.Methods:Randomly collected female OVE26 mice at 12 and 24 weeks of age and age-matched wild-type FVB mice were fed a normal diet.The mice was divided into 4 groups: FVB-12 weeks,OVE26-12 weeks,FVB-24 weeks and OVE26-24 weeks.Glucose and body weight in each group were measured at regular weekly intervals from the fourth week of life until the mice were executed,and cardiac ultrasound was measured at 12 weeks for FVB-12 weeks and OVE26-12 weeks,and at 12 weeks and 24 weeks for FVB-24 weeks and OVE26-24 weeks,respectively.The hearts were anesthetized and executed by neck amputation,and the heart weights were subsequently collected and recorded;the heart tissue proteins were extracted and the expression levels of molecules related to fibrosis,inflammation and apoptosis were measured by western blotting;IHC staining of the hearts was performed to observe morphological and related molecular changes.Upon accomplishment of animal experiments,cardiomyocytes from SD rats were taken and randomly divided into four groups for cultivation: control group,high glucose group,high glucose+ DMSO group and high glucose + DMSO +(ADU-S100)group.The expression of cGAS-STING pathway in high glucose cells could be confirmed by western blotting technique;the effects of cGAS-STING pathway on fibrosis,pro-inflammatory response,and apoptosis could be determined by administration of STING agonist ADU-S100 in high glucose cellsResults:1.The blood glucose of OVE26 mice was abnormal at an early stage,while myocardial remodeling occurred early in the growth of OVE mice.In the late stage of OVE26 mice,the heart pumping function was impaired.2.cGAS-STING pathway expression was inhibited in the myocardial tissue of OVE26 mice.The expression of cGAS-STING pathway was inhibited before cardiac function was impaired.3,Inflammation,fibrosis and apoptosis were increased in myocardial tissues of OVE26 mice.As in conclusion 2,increased inflammation,fibrosis,and apoptosis in myocardial tissue were not exclusively seen in advanced diabetic cardiomyopathy.4.cGAS-STING pathway expression is inhibited in cardiomyocytes in a high-glucose environment.The application of the STING agonist ADU-S100 resulted in increased expression of some molecules of the cGAS-STING pathway at the level of the cGAS-STING pathway.5.cGAS-STING pathway protects cardiomyocytes in a high-glucose environmentConclusion:Our experimental results support the conclusion that the cGAS-STING pathway may exert an effect in myocardial protection in a diabetic cardiomyopathy model in OVE26 mice,and this effect is not only confined to the late stage of the disease.Therefore,the inclusion of the cGAS-STING pathway in the study of targeted therapies for diabetic cardiomyopathy is highly promising.