Adipose-derived Mesenchymal Stem Cells Alleviating Cardiomyocytes Injury In The Rat Model Of Diabetic Cardiomyopathy

Objective To investigate the effects of mesenchymal stem cells on cardiac injury and heart dysfunction induced by metabolic disorders as well as the underlying mechanisms including the expression of MG53——muscle specific E3 ligase Mitsugumin 53 in diabetic cardiomyopathy in rats.Methods 1.We induced the diabetic cardiomyopathy (DCM) model in rats, and performed four infusions of adipose-derived mesenchymal stem cells (ADMSCs).Blood glucose, OGTTs, IPITTs were tested. Pathological changes were determined by HE, masson, OilO red. Cardiac injury cytokines were examined by Cobus8000. Heart function was determined by echocardiography. The myocardium protein level of MG53,IRS 1, IR, p-Akt were examined by Western blot.2.Neonatal SD rats were prepared for the isolation of primary cardiomyocytes and cells were divided into three groups randomly: ?normal group (Normal); ? high glucose group (HG);?high glucose and ADMSCs culture medium group(HG+ADMSCs-CM).The morphology and cell surface of cardiomyocytes were tested under phase contrast microscope. The mRNA level of ANP, BNP,?-MHC was determined by Q-PCR. On the basis of three, establishing ADMSCs-CM gradient groups(2mL?1mL?0.5mL?0.25mL)for the next research. The cardiomyocytes protein level of MG53,IRS1, IR, p-Akt were examined by Western blot.Results 1. We find that the hyperglycemia and cardiac dysfunction are significantly alleviated in DCM+ADMSCsgroup compared to DCM group, as manifested by reduced blood glucose, improved systolic and diastolic heart function, inhibited interstitial fibrosis and myocardial hypertrophy, and prevented cardiomyocytes injury(P<0.05).DCM rats show a significantly increased expression of MG53, and decreased insulin receptor, insulin receptor substrate 1 (IRS1), and serine phosphorylation of Akt, which exhibit opposite changes to the ADMSC treated group(P<0.01).2. The pulse frequency of cardiomyocytes was significantly decreased, and cell surface and mRNA level of ANP, BNP, ?-MHC were significantly increased in HG group(P<0.01 vs. normal group). The pulse frequency of cardiomyocytes was significantly increased, and cell surface and mRNA level of ANP, BNP, ?-MHC were significantly decreased in HG+ADMSCs-CM group (P<0.05 vs. HG group). With the ADMSCs-CM increasing volume, MG53 protein level was gradually reduced, and IRS1, IR, p-Akt level were gradually increased(P<0.05 2mL group vs. 0.25mL group). The expression of MG53 was negatively correlated with IRS1, IR, p-Akt(r=-0.75, -0.94, -0.84).Conclusions 1. Our results indicate that hyperglycemia is a risk factor for DCM, and cardiac hypertrophy and fibrosis are the main characters of DCM.2. MG53 plays a critical role in DCM. ADMSCs can alleviate the cardiac injury and improve heart dysfunction of DCM rats through secretion, involving their ability to downregulate the overexpression of MG53, and further elevate IR, IRS1,and p-Akt protein levels, which could improve insulin sensitivity and cardiac metabolism.MSCs-CM has the same effect as to MSCs. This indicates that MSCs can play a protective role by cell and secretion.