| ObjectiveMyocardial infarction was a serious disease which endangers human health,and myocardial fibrosis was the key mechanism of the ventricular remodeling with myocardial infarction.Previous studies found that the Traditional Chinese Medicine of supplementing qi and activating blood circulation,Tongguan Capsules could not only inhibit myocardial fibrosis,but improve cardiac function and left ventricular remodeling induced by myocardial infarction.Nevertheless,the mechanism remained unclear.The ACE-Ang?-AT1R axis of RAS system promoted while the ACE2-Ang(1-7)-Mas axis inhibited the myocardial fibrosis induced by myocardial infarction,according to the recent research.As the cardiac fibrosis and ventricular remodeling were induced by the imbalance of ACE-Ang?-AT1R axis and ACE2-Ang(1-7)-Mas axis in heart RAS system.The balance of ACE-Ang?-AT1R axis and ACE2-Ang(1-7)-Mas axis was good for the inhibitory of myocardial fibrosis and ventricular remodeling with myocardial infarction.Therefore,we hypothesized that Tongguan Capsules could inhibit the NOX2-ROS-Rock signal pathway by restoring the balance between ACE-Ang?-AT1R axis and ACE2-Ang(1-7)-Mas axis,thus reducing the collagen synthesis of cardiac fibroblasts,and finally inhibit the ventricular remodeling after myocardial infarction.The research might provide a traditional Chinese theory of supplementing qi and activating blood circulation method for the ventricular remodel ing about myocardial infarction.Furthermore,the research could provide new ideas and targets for the prevention and treatment of ventricular remodeling after myocardial infarction.MethodsSD rats were used to establish the model of ventricular remodeling after acute myocardial infarction by ligation of left anterior descending coronary artery.The model was divided into 5 groups:control group,operation group,operation+Tongguan Capsules group,operation+ Tongguan Capsules+A779 group,and operation+ACEI group.Small animal ultrasound was used to detect and evaluate the changes of cardiac morphology and function;the whole heart weight/body mass index and hydroxyproline content were detected to understand the situation of cardiac fibrosis;HE staining was used to observe cardiac pathology;the degree of myocardial fibrosis was observed by Masson staining;the expression of collagen was detected by immunohistochemistry and western blotting.The levels of Ang? and Ang(1-7)in serum and heart tissue were detected by radioimmunoassay or ELISA,the levels of ACE,AT1R,ACE2 and MAS were detected by Western blot,and the expression levels of ACE and ACE2 were detected by immunohistochemistry.Immunoblotting was used to detect the expression of NOX2 and Rock2,pull-down was used to detect the expression level of ROS(H202).In vitro cell experiments,through the combination of Ang? and pathway molecular inhibitors,which were used to intervene the cells,Ang? was observed by activating Nox2-Ros-Rock2 pathway to analyze whether Ang? could promote the collagen synthesis of fibroblasts,and whether Ang(1-7)could inhibit the above effects of Ang?.And to clarify that Nox2-Ros-Rock2 pathway was the downstream signal pathway for RAS system to regulate collagen synthesis of cardiac fibroblasts.At the same time,the content of ACE,AT1R,ACE2 and MAS could be detected by immunoblotting,and the expression of molecules and collagen in Nox2-Ros-Rock2 signal pathway could also be detected.ResultsCompared with the control group,Tongguan Capsules can reduce the area of myocardial infarction and myocardial fibrosis,and improve the systolic and diastolic function of the heart.At the same time,it can also reduce the apoptosis of cardiomyocytes,which was proved that RAS system was involved in the pathway of myocardial infarction,and Tongguan Capsules could improve the apoptosis of cardiomyocytes.Operation+Tongguan Capsules group could effectively reduce the expression of collagenl protein after ligation of left anterior descending branch of coronary artery,which showed that Tongguan capsules had the same effect as ACEI,it could reduce the expression of myocardial fibrosis,and could reduce the level of Ang? protein in serum and myocardial cells of myocardial infarction rats.The level of Ang(1-7)protein was significantly up-regulated,the difference was statistically significant(P<0.05),indicating that Tongguan Capsules could not only produce the effect of bidirectional adjustment.At the cellular level,Tongguan Capsules could effectively reduce the expression of NOX2,Rock2 protein after ligation of left anterior descending coronary artery,and significantly decrease the content of H202 in myocardial cells.Western blotting showed that the expression of collagenl protein in Ang?+Tongguan Capsules group and Ang?+tanshinone ?A group decreased significantly.At the same time,compared with Ang? group,Ang?+DPI group,Ang?+NAC group,Ang?+Y27632 could reduce the expression of AT1R,and the expression of AT1R in Ang?+ang(1-7)group and Ang?+Tongguan capsules group also decreased significantly.This further showed that Ang? could aggravate myocardial fibrosis when oxidative stress pathway was inhibited,and Tongguan Capsules could regulate ACE and ACE2 axis in both directions,which improved the process of myocardial fibrosis and ventricular remodeling after myocardial infarction.ConclusionThrough the regulation of the RAS signal pathway,in which it could inhibit the ACE-Ang?-AT1R axis and promote the ACE2-Ang(1-7)-MAS axis,Tongguan Capsules alleviated the influence of myocardial fibrosis and ventricular remodeling after acute myocardial infarction.In view of this mechanism,the study investigated the effect of Tongguan Capsules on postponing or improving the ventricular remodeling after myocardial infarction,and found that Tongguan Capsules could regulate the RAS signal pathway in both directions,and slow down the oxidative stress,so as to improve the synthesis of collagen.These findings provided a theoretical basis for further exploration of Tongguan Capsules as an effective drug in the treatment of myocardial remodeling,Tongguan capsules on arterial system diseases was a significant research direction in the future. |
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