| Myocardial damage caused by diabetes occurs in the early stage,mainly manifested as impaired ventricular diastolic function and decreased compliance.With the aggravation of the disease,abnormal left ventricular systolic function occurs,and finally heart failure occurs.The mechanism of myocardial injury caused by hyperglycemia is very complex and has not been fully discovered.Autophagy is involved in the recycling process of damaged organelles and is frequently impaired in the diabetic heart.Both autophagy injury and excessive activation can lead to myocardial injury in diabetic mellitus.Regulating autophagy is beneficial to the recovery of myocardial homeostasis,thereby reducing the damage of diabetic cardiomyocytes.Regulating autophagy may be a potential strategie for effective treatment of diabetes-induced myocardial injury.Neuregulin-4(Nrg4)participates in a variety of biological functions of the body,and also has a strong regulatory function on glucose and lipid metabolism.Clinical studies have found that Nrg4 is closely related to metabolic diseases.The m RNA expression of Nrg4 in adipose tissue of diabetic patients is decreased,and the serum level of Nrg4 in these patients is significantly lower than that in healthy people.It is speculated that low level of Nrg4 may play an important role in the occurrence and development of diabetes.Despite these findings,little is known about the molecular mechanisms involved.Recent studies have shown that Nrg4 can alleviate high-fat injury of liver cells by activating AMPK/ mTOR signaling pathway and up-regulating autophagy.This suggests that Nrg4 may play a beneficial role by regulating autophagy.Autophagy dysfunction is also closely related to diabetic myocardial injury,and the AMPK/mTOR upstream signaling pathway of autophagy is also considered as a potential target for the treatment of diabetic cardiomyopathy.In summary,this study aimed to investigate the protective effect of Nrg4 on diabetic myocardial injury through regulating autophagy and its possible mechanism.It mainly includes the following parts:Part One Changes of serum Nrg4 levels in diabetic patients with left ventricular diastolic dysfunctionObjective: To investigate the incidence of left ventricular diastolic dysfunction in diabetic patients,and compare the serum Nrg4 levels in diabetic patients with left ventricular diastolic dysfunction,diabetic patients and healthy controls.Methods:1.Echocardiography was performed in diabetic patients and healthy controls,and the incidence of left ventricular diastolic dysfunction was calculated in the two groups.2.Serum Nrg4 levels were measured and compared in diabetic patients with left ventricular diastolic dysfunction,diabetic patients and healthy controls.Results:1.The proportion of left ventricular diastolic dysfunction in diabetic patients was 29.5%,which was significantly higher than that in healthy controls.2.Serum Nrg4 levels were lower in patients with diabetes than that in healthy controls,whereas decreases were more pronounced in patients with left ventricular diastolic dysfunction.Conclusions: The serum Nrg4 level is decreased in diabetic patients,and diabetic patients with left ventricular diastolic dysfunction have further decreased serum Nrg4 levels.Part Two Nrg4 plays a protective role in myocardial injury induced by diabetesObjective: To investigate the protective effect of Nrg4 against diabesis-induced myocardial injury by establishing the mice model of type 1diabetic cardiomyopathy,Methods:1.The mice of type 1 diabetes model were established by intraperitoneal injection of STZ.Four weeks later,the mice with cardiac dysfunction detected by echocardiography were used as the model of diabetic cardiomyopathy.2.Mice were divided into four groups: CON group,DCM group,DCM+Nrg4 group and CON+Nrg4 group.DCM+Nrg4 group and CON+Nrg4group were intraperitoneally injected with Nrg4 recombinant protein for 4weeks.After echocardiography was performed again,the mice were sacrificed and the heart tissues were collected for further detection.3.HE and Masson staining were used to observe the myocardial cells and myocardial fibrosis in each group.Western blot was used to detect apoptotic proteins to evaluate the apoptosis of myocardial cells in each group.Results:1.Diabetic cardiomyopathy mice showed cardiac enlargement,and Nrg4 intervention improved the cardiac hypertrophy.2.Nrg4 intervention improved cardiac function,reduced myocardial fibrosis and reduced myocardial cell apoptosis in diabetic cardiomyopathy mice.Conclusions:Nrg4 alleviates myocardial injury in diabetic cardiomyopathy mice and has a protective effect against myocardial injury caused by diabetes.Part Three The protective effect of Nrg4 against diabetic myocardial injury is related to the regulation of autophagyObjective: To observe the effect of Nrg4 intervention on autophagy in primary mouse cardiomyocytes cultured with high glucose,and investigate the relationship between the cardioprotective effects of Nrg4 and autophagy in the mice model of diabetic cardiomyopathy.Methods:1.Primary cardiomyocytes of neonatal mice were extracted and cultured in different groups,and the changes of cardiomyocyte autophagy in high glucose environment were observed.2.Nrg-4 was used to treat primary cardiomyocytes cultured in high glucose,and its effect on autophagy was observed.3.Autophagy inhibitor(3-MA)and Nrg4 were used to treat diabetic cardiomyopathy mice,and the changes of autophagy,myocardial cell apoptosis,interstitial fibrosis and cardiac function were observed.Results:1.Autophagy was inhibited in cardiomyocytes cultured with high glucose environment.2.Nrg-4 upregulated the autophagy level of cardiomyocytes in high glucose environment.3.3-MA attenuated Nrg4-upregulated autophagy and the protective effect of Nrg4 against diabetic cardiomyopathy.Conclusions: The protective effect of Nrg4 against diabetic myocardial injury is related to the regulation of autophagy.In type 1 diabetes mellitus,Nrg4 exerts a protective effect against diabetic myocardial injury by up-regulating autophagy.Part Four Nrg4 plays a protective role in diabetic myocardium by activating autophagy through AMPK/mTOR pathwayObjective: To observe the effect of Nrg4 intervention on AMPK/mTOR signaling pathway,and demonstrate Nrg4 exerts its protective effect against diabetic myocardial injury by activating autophagy through the AMPK/mTOR pathway.Methods:1.Primary cardiomyocytes were cultured in high glucose environment to observe the effect of Nrg4 intervention on AMPK/ mTOR signaling pathway.2.AMPK inhibitor and Nrg4 were used to simultaneously intervene in cardiomyocytes in high glucose environment,and the changes of autophagy and cardiomyocytes apoptosis were observed.Results:1.Nrg4 activated AMPK/mTOR signaling pathway.2.AMPK inhibitors blocked Nrg4-activated autophagy.3.AMPK inhibitor attenuated the protective effect of Nrg4 on cardiomyocytes apoptosis induced by high glucose.Conclusions: Nrg4 activates autophagy through AMPK/mTOR signaling pathway and exerts its protective effect against diabetic myocardial injury in high glucose environment. |
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