| Depression and coronary heart disease are serious threats to the physical and mental health of human beings;they act upon each other and have causality between them.They affect each other’s occurrence,development and prognosis.Depression is an independent risk factor for the development of coronary heart disease and can aggravate the condition of patients with coronary heart disease.Death is frequent in serious adverse events,and the prognosis is often worse.Patients with coronary heart disease is also a high-risk group of depression.Double heart treatment has been widely used for clinical medical treatment at home and abroad.In order to investigate the mechanism of Kaixin san on double heart disease(coronary heart disease combined with depression or depression combined with coronary heart disease),a rat model of chronic unpredictable stress model was adopted to observe behavioral indicators such as weight of the rats,OFT,SFT,and FST.A rat model of depression complicated with myocardial ischemia model was used to observe the effects of Kaixin san on serum content of CK and LDH,ECG,echocardiography,pathological biopsy and the expression of Bax and Bcl-2 in the heart.To investigate the effects of Kainxin san on SOD,MDA,CAT,GSH-PX,IL-6 and inflammatory cytokines such as CRP and TNF-a in blood and heart tissues of rat model,we aim to explore the mechanism of Kaixin San against depression and on protection of myocardial injury,and to provide a theoretical basis for the clinical application of Kaixin san in the treatment of double heart disease(coronary heart disease combined with depression or depression combined with coronary heart disease).Objective:Based on the rat chronic unpredictable stress model(CUMS),a complex model of depression combined with myocardial ischemia was established to observe the antidepressant effect of Kaixinsan on rats of complex model and the protection on cardiomyocytes and heart function.Molecular biology methods were used to explore the mechanism of Kaixinsan anti-depression and its possible protective effect on the heart from the molecular and cellular levels of anti-oxidation,anti-inflammation,anti-apoptosis and protein expression.Methods:To establish the rat model of depression by the CUMS,the rats were given Kaixin san and the positive drug for 14 days.To cause acute cardiac ischemia and establish the depression with myocardial ischemia rat model,the rats were given continuous intraperitoneal injection of isopropyl adrenaline at the end of administration.The depressive states of each group were assessed by behavioral indicators such as weight of the rats,OFT,SFT,and FST.Elisa method was used to detect the contents of 5-HT in serum and hippocampus of rats.The behavior indicators,electrocardiogram,echocardiography,pathological biopsy and contents of serum CK and LDH were adopted to evaluate rationality of the model and to explore Kaixin san’s potential protective effect and mechanism on damaged myocardium.By study the effect of SOD,MDA,CAT,GSH-PX in the blood and heart tissues of complex model of rats and the contents of CRP,IL-6 and TNF-a in heart tissues.To investigate the potential mechanism of Kaixin san on protection of the damaged heart muscle and anti-apoptosis effects in complex model,Tunel method was used to detect myocardial apoptosis cells in each group of rats.By immunehistochemical method and western blotting method,the expression of Bax and Bcl-2 was observed in the heart of rats.Results:The experimental results showed that on the basis of the depression model,difficulty breathing,unstable heart rate,and the state of nasal bleeding were observed in some rat after intraperitoneal injection of isoproterepinephrine.Compared with normal control group,OFT scores,SFT and weight were significantly decreased,while swimming time increased obviously in model group.After the treatment,compared with model group,the scores of OFT,SFT and FST increased prominently in Kaixin san group and positive medicine group,while the swimming time was significantly reduced,with statistical significance(P<0.01).The results of HE staining showed that after the injection of isoproterenol and saline,the structure of the heart in the normal control group had no obvious abnormalities.Myocardial ischemia model group and depression combined myocardial ischemia model rats had extensive cardiomyocyte injury,necrosis in the heart,interstitial fibrosis in the myocardium,interstitial fibrosis,visible loose connective tissue,diffuse infiltration of inflammatory cells,and capillaries hyperplasia.Hyperplasia,myocardial cell cytoplasm vacuoles,and some muscle sarcoplasmic necrosis.Compared with the complex model group,the myocardial pathology in the complex model group(Kaxin san)and the positive drug(Metoprolol)group was significantly improved.In addition to the normal control group,the rest of the groups had varying degrees of changes in electrocardiogram and echocardiography.Compared with the normal group,the values of EF and FS decreased significantly in the myocardial ischemia model group and the complex model group,and there was a statistically significant difference between the groups(P<0.01).At the same time,the values of EF and FS in the depression model group were also lower than those in the normal control group.There was a statistically significant difference between the groups(P<0.01),but it was much higher than that in the myocardial ischemia model group and the complex model group.Compared with the normal control group,IVS;d,IVS;s,LVPW;s,and LVPW;d were increased markedly in the myocardial ischemia model group and the complex model group(P<0.01)while LVID;d,and LVID;s were decreased significantly(P<0.01).Compared with normal control group,the activity of SOD,GSH-Px and CAT decreased significantly and MDA content was significantly increased with statistical significance in serum and cardiac tissue of depression with myocardial ischemia rat model(P<0.01).Kaixin san could increase activity of SOD,GSH-Px and CAT significantly in rat serum and myocardial tissue,decrease MDA content outstandingly,which indicated antioxidation of Kaixin san may be one of the mechanisms that protect the heart.Compared with the control group,the levels of CRP,IL-6 and TNF-a in the serum and myocardial tissues in depression combined with myocardial ischemia rat model were significantly higher,with statistically significant(P<0.01).The contents of CRP,IL-6 and TNF-a in serum and myocardial tissue in rat model were obtained and played an anti-inflammatory role.Tunel experimental results showed that the apoptosis of normal cardiomyocytes was 8%.Compared with the normal control group,the apoptotic index of cardiomyocytes in each model group was significantly increased,and the complex model group was as high as 38%(P<0.01).Compared with the model group,the apoptotic index of myocardium in the treatment group was significantly decreased,and the apoptotic index of the myocardium in the complex model group was 20%(P<0.01),indicating that Kaixin san can inhibit the apoptosis of cardiomyocytes and thereby protect the heart.The results of immunohistochemistry showed that the positive expression of Bax protein in the normal control group was rare.The positive expression of Bax protein was significantly increased in the model group and was highest in the cytoplasm which was yellowish brown.Compared with the model group,Kaixin san group could significantly reduce the expression of Bax protein in cardiomyocytes,and there was a statistically significant difference between groups(P<0.01 and P<0.05).Bcl-2 protein was highly expressed in the normal control group,and the positive expression in the model group was significantly decreased.Compared with the model group,the Kaixin San group significantly up-regulated the expression of Bcl-2 protein in cardiomyocytes,and there was a statistically significant difference between the groups(P<0.01 and P<0.05).Conclusion:Using the CUMS model and depression with myocardial ischemia model,this research evaluated pharmacological functions and mechanism of Kaix:in san.It was found Kaixin san has a certain protective effect on the heart besides anti-depression.Its mechanism of action is closely related to the activity of antioxidant enzymes,inhibition of inflammatory factor expression and regulation of related apoptotic protein levels.In addition,the indicators of myocardial depression model group rats were slightly lower than those of the normal control group,demonstrating that chronic stress has a certain influence on rat heart,which changed the myocardial function in depression rats,and suggested the depression may be the potential risk factor for cardiovascular disease. |
PDF Full Text Request