Progression And Sexual Difference Of Diabetic Cardiomyopathy In OVE26 Type 1 Diabetic Mice

Background:Diabetes has a long course and a high incidence,which seriously threatens human quality of life and health.Diabetes complications accumulate tissues such as heart,eye,brain,kidney,and nerves.As an important complication of diabetes,diabetic cardiomyopathy often causes myocardial dysfunction due to abnormal myocardial structure and reduced contractility.OVE26 mice are a widely used transgenic model of early onset type 1 diabetes.These mice overexpress calmodulin in their pancreatic β cells,develop severe diabetes within the first weeks of life,and progress to severe diabetic complications including diabetic nephropathy and diabetic cardiomyopathy(DCM).To date,diabetic nephropathy in OVE26 mice have been well explored,leaving the progression of DCM and the gender impact in this type 1 diabetes model still unrevealed.Object:To study the progression of diabetic cardiomyopathy and gender differences in type 1 diabetes model OVE26 mice.Methods:Male and female OVE26 mice and age-matched wild-type FVB mice were randomly selected and given a normal diet.The mice were divided into 4 experimental groups,namely FVB-female,FVB-male,OVE26-female,and OVE26-male.Five to eight mice in each group were selected to measure blood glucose and body weight at the time points of 4 weeks,12 weeks,24 weeks,30 weeks,and 36 weeks,and cardiac function was measured by cardiac ultrasound.The mice were anesthetized and sacrificed,and the hearts were collected.For pathological tests,molecular biology and mitochondrial function tests.Specific detection methods include: measuring mouse body weight,blood glucose,heart weight to tibia length ratio;HE staining and Sirius Red staining;immunoblotting to detect fibrosis(collagen I,FN-1),oxidative stress and injury(CAT,SOD2,3-NT,4-HNE),inflammatory response(Il-1β,VCAM-1,ICAM-1),aging and SASP-related protein factors(P53,P21,P16,MMP12,P38,ERK and AKT),etc.Indicators;Extracellular flow cytometry was used to determine the functions of mitochondrial complex enzyme I and mitochondrial complex enzyme II.Results:Both male and female OVE26 mice developed hyperglycemia at 4 weeks of age,and hyperglycemia continued at> 450 mg / dl throughout their life cycle.FVB mice did not show significant cardiac damage during the progression from 4 to 36 weeks.Compared to FVB mice,OVE26 mice had worse cardiac function after 24 weeks,with lower FS values and EF.Value,more severe fibrosis,more severe inflammation,oxidative stress,and aging.After 24 weeks,OVE26 T1 D mice developed cardiac fibrosis or at least partial cardiac fibrosis.Col-1 accumulation was evident in OVE26 mice.Compared with FVB mice,FN expression in OVE26 mice was significantly higher at 36 weeks than in their sex-matched FVB group.Compared to FVB mice of the same age and sex,3-NT expression increased in 24-week male OVE26 mice and 36-week female OVE26 mice,while 4-HNE increased significantly in only 36-week male OVE26.The expression of Il-1β in female and female OVE26 mice was significantly higher than that of FVB at 36 weeks.VCAM expression in OVE26 female mice was significantly higher than that in FVB females at 36 weeks,and at 24 and 36 weeks in males.Male and female OVE26 mice had significantly higher ICAM expression at week 24 and 36.The expression of p53 and p21 increased in female OVE26 mice after 24 weeks,while p53 was also found to increase from 24 weeks to 36 weeks in male mice,while the expression of p21 increased significantly only at 24 weeks.In female and male OVE26 mice,p16 expression increased only at 36 weeks.MMP12 expression was higher in OVE26 mice at 24 weeks.The mitochondrial complex enzyme I and complex enzyme II functions of OVE26 mice were not impaired at 12 and 24 weeks.The trauma effect of type 1 diabetes in OVE26 mice on the heart of mice began to gradually manifest in the process of 12 to 24 weeks,and the heart damage of female OVE26 mice was more severe than that of male mice.Conclusion:Through cardiac function,tissue section,myocardial fibrosis,and immunoblot analysis of OVE26 mice,this study reports the first time-tracked reports of impaired heart function and dysfunction in diabetic cardiomyopathy caused by female and male OVE26 mice.In the heart of type 1 diabetes model OVE26 mice,there are manifestations of cardiac function abnormalities,myocardial fibrosis,hypertrophy,inflammation,oxidative stress injury and aging caused by diabetes.Heart aging and fibrosis may change due to gender differences and play a key role in the process of diabetic cardiomyopathy in OVE26 mice.The function of mitochondrial complex enzyme I and mitochondrial complex enzyme II in the mitochondrial respiratory chain of OVE26 mice is not abnormal,which excludes the direction for future mitochondrial dysfunction research.The comprehensive characterization of diabetic cardiomyopathy progression and the sex difference impact in OVE26 mice provides a basis for future study on DCM using OVE26 mice.