Mechanism Of Ang Ⅱ Activated JAK/STAT Signaling Pathway In Atrial Fibrillation

PartⅠ:Mechanism of AngⅡ activated JAK/STAT signaling pathway in myocardial remodeling of Atrial Fibrillation.Background Currently,Atrial Fibrillation(AF)is the most common sustained arrhythmia in the world.AF often occurs repeatedly,which may lead to atrial thrombosis and stroke,with serious influence on patients’ quality of life.Repeated attack of AF can not only cause disordered conduction of atrial electrical excitement,but can also trigger excessive activation of renin-angiotensin system(RAS)in atrial tissues,leading to myocardial remodeling characterized by atrial enlargement and myocardial fibrosis,which will further aggravate the disordered atrial electrical conduction and form anatomical basis for the recurrence and maintenance of AF.If the relationship of RAS excessive activation with the generation and development of tissue remodeling in atrial tissues during AF can be elucidated,effective intervention can be adopted to eliminate the anatomical basis of AF recurrence at tissue level,and then avoid the sustaining and repeated attack of AF.It has been known that RAS plays a crucial role in regulating the adaptive growth of myocardium.Studies on RAS and myocardial remodeling mainly focus on myocardial protection induced by ischemic preconditioning,heart failure caused by ischemia-reperfusion,and other fields,but little has been reported on the mechanisms of RAS excessive activation and myocardial remodeling during AF.Taking patients with valvular heart disease who underwent mitral valve replacement surgery as subjects,the present study aimed to investigate the mechanism of Ang Ⅱactivated JAK/STAT signaling pathway in myocardial remodeling of AF patients through detecting the Ang level in peripheral Ⅱcirculation and the Ang and JAKⅡ 、STAT level in tissues.Objective To investigate the mechanism of Ang activated JAK/STAT signaling pathway Ⅱin myocardial remodeling of AF.Methods A total of 30 patients with valvular heart disease who underwent mitral valve replacement surgery were selected as subjects(Patients taking ACEIsand/or ARBwere excluded from the study),among whom 17 cases with AF were assigned into the experimental group and the other 13 cases without AF were assigned into the control group.Before operation,AngⅡin peripheral circulation was detected.In the operation,the resected left auricle was sampled and treated,after which Ang Ⅱ in tissues was detected using ELISA;JAK、STAT、myocadial fibrosis degree in left auricle tissues was also detected using Western blot、EMSA、Masson and so on。Results AngⅡof experimental group before operation was significantly higher than that of control group(P<0.01);AngⅡand JAK1、STAT3 in the myocardial tissues of experimental group were significantly higher than those of control group(P<0.01,P<0.01).Experimentaltissue display the deposition of collagen fiber,the hyperplasia of connective tissue under the endocardium and stroma,even visible inflammatory cells。There are significantly statistical differences between two groups(P< 0.01)Conclusion The AngⅡ and JAK1/STAT3 in the myocardial tissues of AF patients were significantly higher than those of non-AF patients,suggesting that RAS excessive activate JAK1/STAT3 in the atrial tissues of AF patients is associated with the generation and development of myocardial remodeling.Part ⅡEffect of ACEI on Ang II activated JAK/STAT signaling pathway in persistent Atrial Fibrillation modelBackground Atrial fibrillation(AF)is a common abnormal atrial electrical activity.AF has a certain degree of self-maintenance,the probability of successful cardioversion decreases with the prolongation of attack time,and the ability to maintain sinus rhythm also decreases,which brings much difficulty to the treatment of AF patients.Although there are multiple treatment methods for AF in clinical practice,such as antiarrhythmic drug treatment,interventional radiofrequency ablation treatment and surgical treatment,the therapeutic effects of these treatment methods on AF patients are still unsatisfactory.Relevant studies on AF have demonstrated that the excessive activation of rennin-angiotensin system plays an important role in the generation and development of AF.Previous experiments also demonstrated that Ang II is involved in the myocardial remodeling of AF through JAK1/STAT3 signaling pathway.However,for the prevention of AF,whether using ACEI in clinical practice can reduce the risk of AF still requires further study,as well as the effect of ACEI on AF.Object The present study aimed to investigate the changes of AngⅡ、JAK1、STAT3 and myocardial fibrosis after ACEI prevention and treatment.Methods A total of 55 New Zealand rabbits were divided into 4 groups: 10 rabbits of control group(group A)received pacemaker implantation without pace-making;15 rabbits of AF group(group B)received pacemaker implantation and high frequency pace-making;15 rabbits of experimental group 1(group C)received pacemaker implantation and high frequency pace-making,and two weeks later,captopril was infused by gavage at a dose of 12.5mg/(kg·d);15 rabbits of experimental group 2(group D)received pacemaker implantation and high frequency pace-making,and captopril was infused at the same time.For 4 groups of rabbits,the chest was opened after anesthesia,and pacemaker was implanted below the endocardium of left auricle.The experiment of 4 groups lasted for about 6 weeks.The rabbits were sacrificed 6 weeks later,and left auricle tissues were collected for ELISA,Western blot,EMSA and other tests to determine AngⅡ,JAK1,STAT3,myocardial fibrosis degree,etc.Results In this survey,Ang II,JAK1,STAT3 and ECM% were found to increase in left auricle cardiomyocytes of rabbit models with persistent atrial fibrillation induced by rapid pacing compared with the control group.Given captopril,Ang II,JAK1,STAT3 and ECM% decreased more significantly than the group with atrial fibrillation,while the degree of myocardial fibrosis became lower.Statistically significant differences existed in Ang II,JAK1,STAT3 and ECM% among group Aandgroup B、group A and group C(P<0.01).The differences in Ang II,JAK1,STAT3 and ECM% were also statistically significant between group D andgroup B、group Dandgroup C(P<0.01),so were they in ECM% between groups C and group B(P<0.01).In group B,STAT3 was phosphorylated more easily and translocated to nucleus.With stronger binding capacity,it bound with corresponding genes and thus promoted myocardial remodeling.With the administration of ACEI,capacity of STAT3 for translocation to nucleus and binding could be weakened.The average optical density was significantly higher in group B than all other three groups,and their differences were statistically significant(P<0.01).In addition,group D significantly differed from group B and group C in the average optical density(P<0.01).Conclusions The present study demonstrated that application of ACEI can down-regulate AngⅡ,inhibit JAK/STAT signaling pathway,decrease the fibrosis degree of atrial extracellular matrix and control the myocardial remodeling of AF,thus reducing the generation and development of AF.Earlier intervention of AF can better down-regulate AngⅡ,inhibit RAS and JAK/STAT signaling pathway,decrease the fibrosis degree of atrial extracellular matrix and control the myocardial remodeling of AF.