Anti-arrhythmic Effect Mediated By Wenxinkeli Associated With Cx43Stabilization

Background:The ischemic heart disease currently has the highest mortalityamong cardiovascular diseases. There is an increased incidence whenour country becomes an aging society. Arrhythmia, particularlyventricular arrhythmias induced by myocardial ischemia, are themost important cause of sudden death. So we study the pathogenesisand treatment strategies of ischemia-induced arrhythmia.Uncoupling, which is induced by abnormal structure and functionof Gap junction (GJ), is a key factor in the pathogenesis of ischemicarrhythmia. GJ, which mainly distributes in junctions betweencardiocytes, is the basis of intercellular communication. Becauseits function is to aid in electrical signal coupling and exchangethe chemical signals. Cx43is the major component of GJ in mammals.Recent studies have shown that during cardiocyte-induced ischemia,the increase in oxygen free radicals, calcium overload, acidosis-may lead to the changes of both structure and function of Cx43.Dysfunction of Cx43may lead to uncoupling and reentry, which induce ventricular arrhythmias.On the basis of our study of Wenxinkeli, we further explored ifthe mechanisms of the anti-arrhythmic effect of Wenxinkeli via theCx43pathway. Our results may offer new pharmacological targets forthe prevention and resolution of ischemic heart diseases.We offertheoretical foundations for the clinical use of Wenxinkeli in thetreatment of ischemic heart diseases.Objective:To study whether the anti-arrhythmic effect of Wenxinkeli isaccomplished by regulating the stabilization of structure andfunction of Cx43.Methods:（1）Male Wistar rats were randomly divided into different groups.Myocardial ischemia was induced by temporary occlusion of the leftmain coronary artery. Subdermal electrodes were placed to allow thedetermination of a lead II electrocardiogram (ECG). The tissuespecimen was then preserved.（2）HE analysis was used to investigate the distribution andstructure of cardiomyocytes in ischemic and non ischemic zones.（3）Immunohistochemical analysis was used to investigate the distribution,structure and function of Cx43in ischemic zones.（4）Western blotting analysis was used to investigate contentand function of Cx43in ischemic zones.（5）ELISA was used to investigate content and function of Cx43in ischemic and non ischemic zones.Results:(1) Wenxinkeli, which makes the arrhythmia scores decline, cansignificantly reduce the occurrences of ventricular premature beat(VP), ventricular tachycardia (VT) and ventricular fibrillation(VF), and Obviously diminish the duration of ventriculartachycardia (VT) and ventricular fibrillation (VF). Wenxinkeli caneffectively improve the survival rate of myocardial ischemia rats,and reduce the mortality of myocardial ischemia rats. Thus it provesthat Wenxinkeli can effectively inhibit the occurrences of ischemicventricular arrhythmias in rats, and shorten the duration ofischemic ventricular arrhythmias, which can improve the survivalrate of rats.(2) It is found that Wenxinkeli can effectively prevent thenecrosis of myocardial cells, and reduce the occurrences of ischemicarrhythmias in rats by HE dyeing observation. (3) The resistance of Wenxinkeli to ischemic arrhythmias isassociated with Cx43protein. In the control group rats,the Cx43of ventricular muscle tissue mainly distributed in myocardialintercalated disc area, and rarely distributed in the lateral ofmyocardial cells. After ischemia reperfusion in model group rats,the Cx43dishes to the lateral displacement in myocardial cells frommyocardial embellish in myocardial tissue. And with the amount ofCx43protein decreasing, the phosphorylation levels drop, so thatarrhythmia scores rise. The structure and function of Cx43proteinin Wenxinkeli group rats gradually restored, and the expressionand phosphorylation levels of Cx43protein increased, so thatarrhythmia scores decline. Wenxinkeli increased the expression andphosphorylation levels of Cx43protein in the ischemia area, soas to play the role of resistance to ischemic arrhythmias, and hadno obvious effect in the non ischemic zone.Conclusions:(1) The study proves the changes of the structure and functionof Cx43protein during myocardial ischemia/reperfusion.(2) Comparing ischemic zones with non ischemic zones in rats,we found that Wenxinkeli can adjust the stability of the structureand function of Cx43protein in ischemic myocardial cells to resist to the cardiac arrhythmias.Innovations:(1) We find that Wenxinkeli plays a role of resistance toischemic arrhythmias by regulating the stability of Cx43protein.(2) Comparing ischemic zones with non ischemic zones in rats,Wenxinkeli plays a role of resistance to ischemic arrhythmias byregulating the stability of Cx43protein.