The Effect Of Intensive Statin Therapy On Inflammatory Reaction And Myocardial Fibrosis After Myocardial Infarction In Rats

Backgroud and Objective Acute myocardial infarction (AMI) is myocardial necrosis caused by acute, persistent ischemia and hypoxia. Hypoxia, hemodynamics changing, wall tension increasing and neuroendocrine abnormalities after myocardial infarction can induce the inflammatory response. The abnormal increasing of inflammatory factors will contribute to excessive accumulation or significantly increase concentration or change components of collagen fibers. Research has shown that inflammatory response plays an important role in the development of myocardial fibrosis. But currently the exact mechanism of inflammatory response leading to myocardial fibrosis is still not very clear. Epithelial-mesenchymal transition(EMT) is the biological process which Epithelial cells get through a specific program into cells with mesenchymal phenotype. Into the body, EMT is closely related to the formation of fibroblasts in wound healing, tissue regeneration and organ fibrosis. Among them, the one associated with damage repair, tissue regeneration and organ fibrosis is defined as 2 type EMT. This type of EMT is the important part of the event related to injury, and its main biological function is to produce fibroblast cells to repair the wounds and tissue damage caused by inflammatory reaction. In the case of continuous activation of inflammatory, the EMT process persists presence, and eventually leading to organ fibrosis. In the EMT, the transcription factors Snail and the E-cadherin are very important biomarkers. As a number of common downstream signaling pathways target, Snail is widely involved in development, tumor and fibrosis. The downregulation expression of E cadherin as biomarkers of EMT is widely used in various types of research in EMT, at the same time, E-cadherin loss also further promote the progress of EMT. Currently, the research for the EMT is mainly in renal fibrosis, pulmonary fibrosis and tumor metastasis. Whether myocardial fibrosis process involving EMT is not sufficient. Statins is the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which is the based drug widely used in clinical anti- atherosclerosis. A large number of studies have shown that lowering LDL-C is the base benefit of statin. Depth study of statin found that when lowering cholesterol statin has a pleiotropic effects. The pleiotropic mechanism may be unrelated to its lipid-lowering effects, as has been observed that when the lipid-lowering effect has not shown that the pleiotropic effects have been appearing, which are including increasing the bioavailability of nitric oxide, repairing damaged endothelium, anti-inflammation, atherosclerotic plaque stability, anti-arrhythmia. Research has shown that statins have the role of anti-inflammatory and reversal of myocardial remodeling, but the mechanisms remain unclear. So This topic is intended to make rats myocardial infarction as a model to study the inflammatory reaction, myocardial fibrosis and EMT biomarkers changes after myocardial infarction to evaluate the effect of intensive statin therapy on inflammatory reaction and myocardial fibrosis after myocardial infarction in rats.Methods 24 SD rats were randomly divided into 3 groups(intensive statin group, general dose group,each group had 8) and added 8 SD rats to be sham-operated group. Established AMI rat model by ligation of left anterior descending branch of coronary artery. In intensive group, atorvastatin was fed by 50mg·kg-1·d-1 with distilled water 1.5ml, general dose group was fed by 20mg·kg-1·d-1 with distilled water 1.5ml, the other two groups were fed with the same amount of distilled water, continued until 4 weeks after surgery. (1) In the first part: each group were collected venous blood at retinal venous plexus by capillary 3 days before surgery (before treatment) and 4 weeks after surgery. Separated serum and used chemiluminescence to measure interleukin-6 (IL-6), used immunofluorescence to measure tumor necrosis factor-α(TNF-α). (2) The second part of the experiment: Executed the rats in each group 4 weeks after surgery and retained the left ventricle of the heart (infarct zone and infarct border zone). HE staining to understand the infarction situation, masson staining to understand myocardial fibrosis, immunofluorescence to understand E cadherin and immunohistochemical to understan Snail.Results (1) The inflammatory factor IL-6 and TNF-α: Each group did not differ on pairwise comparison in preoperative; Control group was significant higher than the sham group, atorvastatin therapy can inhibit inflammation after myocardial infarction, and the large dose was better than the general dose. (2) HE staining: The infarct zone was significant in intensive group, general group and control group. masson staining: intensive group, general group and control group can be found out the myocardial fibrosis, the control group was the most significant. Atorvastatin therapy can inhibit myocardial fibrosis after myocardial infarction, and the large dose was better than the general dose. The test result of E cadherin showed that the intensive group weak express in the epicardium, the general group was weaker than intensive group, the control group did not express, the sham group can be seen E cadherin express in the epicardium. The test result of Snail showed that the intensive group weak positive expression, the general group was stronger than intensive group, the control group positive expression and there was no expression in the sham group.Conclusion (1) Myocardial infarction has a significant inflammatory process, atorvastatin therapy can inhibit myocardial fibrosis significantly after myocardial infarction, and the large dose was better than the general dose. (2) There was significant myocardial fibrosis after myocardial infarction, EMT maybe involve in the process of the myocardial fibrosis. Atorvastatin therapy can inhibit myocardial fibrosis after myocardial infarction, and the large dose was better than the general dose.