| Diabetes Mellitus is a kind of metabolic disease characterized by insulin secretion and impaired utilization and chronic hyperglycemia. Diabetes is now considered to be one of the major risk factors for cardiovascular disease. "The experiment of established model of diabetic minipig with ischemia-reperfusion myocardium" in the former part also showed that infarction area in diabetes group after surgery is significantly greater than that in the control group, and the complication rate is also significantly higher than that in the control group. Clinical studies also showed that the incidence rate and mortality of MACE events after revascularization for patient with coronary heart disease and diabetes mellitus is significantly higher than non-diabetic patients, which is closely related to poor tolerance of diabetic type of myocardial ischemia-reperfusion. Hence, how to alleviate injury of diabetic patients with ischemia-reperfusion; and reduce myocardial cell apoptosis is an important clinical problem.As for poor tolerance in diabetic patients with myocardial ischemia, looking for markers of potential myocardial ischemia and potential therapeutic targets would be great help to the prognosis of these patients. Hence, based on the scientific fact that small molecule metabolites can timely reflect the injury state of myocardial tissue to DM and ischemia-reperfusion, this study firstly uses the previous animal model specimens, by the method of metabolomics, and screens metabolites with differences in micromolecules of combined DM and myocardial ischemia-reperfusion injury. It has been found that there are 12and 26 metabolites with differences in myocardium and coronary sinus blood respectively, mainly related to pathways such as sugar, protein and fat metabolism, antioxidant stress, which suggests that these metabolites all play an important role in diabetic-type of myocardial ischemia reperfusion.Among the discovered differential metabolites, Gln is reduced extremely significant (lower down 59.4% and 73.4% respectively) in myocardium and coronary sinus blood respectively, which prompts that Gln has played a key role in the progress of the disease. Recent literature also shows the protective effect of Gln on ischemia reperfusion cell. But in the case of diabetes pathology, whether Gln also has a protective effect and concrete mechanism has not been reported.Then we use H9C2 cardiac muscle cell lines and diabetic rats induced by STZ to study the impact of Gln on ischemia-reperfusion myocardium with diabetes in vivo and in vitro respectively. Based on results, we have found that the Gln could raise the GSH concentration and GSH/GSSG ratio in H9C2 cell mitochondria and cytoplasm, reducing oxidative stress of cells and mitochondria, thereby protecting the mitochondria and reducing apoptosis. In vivo experiments, we have found that Gln could relieve the oxidative stress level of diabetic rats after ischemia-reperfusion, improving myocardial ultrastructure, reducing myocardial infarction area, and improve cardiac systolic and diastolic function after surgery. Thus, Gln has the prospect of becoming a myocardial protective drug for diabetics to reduce risk of ischemia-reperfusion clinically.Animal Models of Human Diseases are the animals with performances of human diseases established in research of biomedical science. The use of animal models is one of the most important experimental method in modern biomedical research, which is useful for the more convenient and efficient perception of human diseases, so as prevent and control the occurrence and development of diseases.With the heavily growth of chinese aging, changes in spectrum of diseases and diet, ischemic heart disease is increasingly become a major disease which poses serious threat to people’s life safety. The study of ischemic heart disease has gradually become a hot spot in the medical community, but the lack of stable, reliable and standardized model of myocardial ischemia disease is the bottleneck of current research in this field.There is a great difference in heart structure and metabolism between rodent animal and humans, while little is between swines and humans. We, in this study, had created and improved the existing material, and had set up the myocardial ischemia model of three kinds of minipigs from three different aspects using minimally invasive techniques (thoracoscope, small incision) and hybrid surgical technique. (1) Model of minipig with ischemic mitral regurgitation:A 2.5-mm ameroid constrictor was placed around the left circumflex coronary artery (LCX) of miniature pigs to induce ischemia, while the posterior mitral chordae tendinae was also ruptured by through a mitral strain device. The model was simulated mitral regurgitation, followed by chronic myocardial ischemia. (2) Model of minipig with chronic myocardial ischemia:By simulating the process of clinical chronic myocardial ischemia disease, based on faults of import Ameroid ring, we had produced modified Ameroid ring, and had placed it around the left circumflex coronary artery (LCX) of miniature pigs under thoracoscope. (3) Model of diabetes with acute myocardial ischemia reperfusion:The case of clinical diabetes with ischemia-reperfusion injury was simulated. We firstly induced diabetic model through intravenous injection of streptozotocin, and implementing ischemia-reperfusion in anterior descending artery under thoracoscope after the successful modeling.According to the characteristics of each model, we had carried on the detailed inspection and assessment for the three kinds of model (e.g., serology, echocardiography and coronary angiography, nuclear magnetism, PET/SPECT, pathology, etc).It had been found that the three myocardial ischemia models established with minimally invasive technology and hybrid technology can better simulate characteristics of human diseases, characterized by good similarity, repeatability and controllability as well as simple and convenient operation, thus they should be used widely applied in the basic experiments and clinical experiments. |
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