| Ventricular remodeling is the result of molecular, cellular and interstitial changes in response to acute myocardial infarction, representing adverse alterations in the size, shape and function of the left ventricle. Ventricular remodeling exists during the whole pathophysiological course of acute myocardial infarction. Recently, some scientists have proposed that ventricular remodeling may be one of the main reasons for the recovery in patients with acute myocardial infarction. Cardiac remodeling after myocardial infarction is a significant pathological basis contributing to eventual heart failure. The systolic, diastolic function damages and structure changes in heart usually affect ventricular remodeling. The progressed cardiac function deterioration is very correlative with ventricular remodeling. The recent studies show that myocardial inflammatory response induced by acute myocardial infarction plays an important role in ventricular remodeling.Nuclear factor NF-κB, a protein that binds specifically to an enhancerκB sequence ofκB immunoglobulin light chain gene, can activate transcription and expression of multiple cytokines by specific binding to their promoter or enhancer regions, and promote inflammation and immunological response, and has been closely correlated with certain important pathological and physiological processes including cell proliferation, transformation and apoptosis. NF-κB plays an important role in the development and progress of some diseases, thus becoming a new research hot spot.The proinflammatory cytokines play an important role in ventricular remodeling. Ventricular remodeling is the result of not only myocardial cell changes but also cardiac interstitial collagen changes. Nuclear factor NF-κB is a proinflammatory transcription factor. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been implicated in the pathogenesis of cardiovascular diseases, including acute myocardial infarction, chronic heart failure,atherosclerosis and viral myocarditis. Angiotensin converting enzyme inhibitor ACEI can improve cardiac function and inhibit ventricular remodeling and myocardial fibrosis.The ventricular remodeling is closely correlated with the proinflammatory cytokine activity TGF-β1 plays an important role in ventricular remodeling. The TGF-β1 participates in the early period of myocardial fibrosis. Many studies show that the TGF-β1 expression increases after infarction , indicating that TGF-β1 plays key role in ventricular remodeling and myocardial fibrosis.The occurrence and development of ventricular remodeling after myocardial infarction are correlated with the increased expression and activation of TNF-αresulting from secondary immune reaction triggered by myocardium injury and ischemia. TNF-αis not expressed or expressed in low level in normal myocardium, but its expression increases significantly in myocardium after infarction. The role of TNF-αin promoting ventricular remodeling lies in promoting the proliferation of fibroblast and secretion of collagen, as well as regulating the expression of matrix metalloproteinase in some extent. Meanwhile, TNF-αhas some correlation with left ventricular function.Under large amount of experiments and clinical studies, some regulation factors of ventricular remodeling have been found from modern medicine, and the prevention of ventricular remodeling by modern medicine and traditional medicine has got great progress. The development of ventricular remodeling after infarction is a complex course, and it is an effective method to prevent it with combination of traditional medicine and western medicine.The main contents of this thesis are as follow:1 The inhibitory effects of tongxinluo on NF-κB expression after myocardial infarction in ratTo investigate the inhibitory effects of tongxinluo on NF-κB expression after infarction in the rats, 80 rats were randomly divided into two groups: Sham operation group and coronary artery ligation group. Sham group was fed with 0.9 % NaCl( n=10, after 4 weeks, n=8), and killed after 4 weeks. 70 rats underwent the left descending coronary artery ligation, 38 surviving rats were randomly assigned to one of the following groups: AMI model group (M group, the rats were fed with 0.9 % NaCl, n=9); high dose tongxinluo group (TH group, 1.0 g kg-1 d-1, n=10), low dose tongxinluo group (TL group, 0.05 g kg-1 d-1); Captopril treatment group (C group, 15 mg kg-1 d-1, n=10). Latter three of all the groups were fed with the medicine for 4 weeks. At the end of the experiment, the animals were weighted. Myocardial infarction areas were quantified by TCC. Electrocardiograms of animals were recorded on the operation. The rat hearts were fixed and pathologically analyzed. Morphological characteristics were evaluated with HE staining. Myocardial ultra-structural and histopathological changes were observed. NF-κB mRNA was detected by reverse transcription- polymerase chain reaction (RT-PCR).Body weight of M group was significantly lower than sham operation group. TH group and C group were significantly higher than M group. Myocardial infarction areas were different. Electrocardiograms (ECG) of 10 animals in the control group were all normal. ECG of 38 animals in the myocardial infarction rats was not normal. ST segment elevated in rats of the myocardial infarction.The myocytes from the control group arranged regularly. The size of the nucleus was uniform. The staining of cytoplasm was homogeneous. The myocytes from the M group arranged irregularly. The nucleus was irregular and the interrupted myofibril was observed. The TH group and C group were obviously improved. The myocytes from TH group and C group arranged more regularly than those from the M group. The interrupted myofibril was not common. The nuclear shape was more regular than the M group.The left ventricular myocytes from the control group arranged regularly. The thick and thin myofilaments arranged regularly. The sarcomere and light-dark band were clear. The pericellular membrane was uninterrupted and intact. The uniformly sized mitochondrion was abundant and showed round or oval shape.The left ventricular myocytes from the M group arranged irregularly. The pericellular membrane was interrupted and unclear. The local myofibril was disintegrated. The mitochondrial shape was abnormal with deep notch. The swelling mitochondria increased and accumulated. The nuclear shape was abnormal with deep notch. The mitochondrion was presented in the form of blank space.Compared with the M group, the ultrastructural shapes of mitochondria in the TH group and C group were obviously improved. The myocytes from the TH group arranged more regularly than the M group. The mitochondrial shape was uniform. The phenomenon indicates that the local myofibril disintegration was decreased. The mitochondria were presented in the form of slightly blank space.The mitochondrial shape was not uniform in TL group. The swelling mitochondria increased and accumulated. The nuclear membrane shape was abnormal with deep notch. The mitochondria were presented in the form of blank space.The positive reaction of NF-κB protein was stained brown and existed in myocardial cytoplasm. There was uniform distribution of weak brown granules in the control group. There were thick brown granules in the M group. The granule of the TH group was weaker than the M group. There was uniform distribution of weak brown granules on NF-κB in the control group. The granule of the M group was thicker than the TH group.Compared to sham operation group, the NF-κB expression was enhanced in M group. The NF-κB expression in the TH group and C group was significantly lower than M group.At M group, NF-κB expression on the myocardium increased after infarction, which suggests that NF-κB plays an important role in ventricular remodeling. In comparison with M group, the NF-κB expression was significantly lower (p<0.01) in the TH group and C group. The inhibitory effects of tongxinluo are based on its anti-oxidative action. The protective effect of tongxinluo on ventricular remodeling may be beneficial. Nuclear factor NF-κB is a proinflammatory transcription factor. The ventricular remodeling is closely correlated with the proinflammatory cytokine activity. 2 The inhibitory effects of tongxinluo on TGF-β1 expression after infarction in ratTo investigate inhibitory effects of tongxinluo on TIFF-β1 expression after infarction in rats, 60 rats were randomly divided into two groups: sham operation group and coronary artery ligation group: Sham operation group was fed with 0.9 % NaCl for 4 weeks (n=10, after 4 weeks, n=8), and killed after 4 weeks; 50 rats underwent the left descending coronary artery ligation, 28 surviving rats were randomly assigned to one of the following groups: AMI model group (M group, the rats were fed with 0.9 % NaCl for 4 weeks, n=9); high dose Tongxinluo group (TH group, 1.0 g kg-1 d-1, n=10), and low dose Tongxinluo group (TL group, 0.05 g kg-1 d-1, n=9). All the groups were fed with the medicine for 4 weeks. At the end of the experiment, the mRNA and protein expression of NF-κB was examined by reverse transcription- polymerase chain reaction (RT-PCR) and immunochemistry.Compared to sham operation rats, the expression of TGF-β1 mRNA and TGF-β1 protein showed significant increase in M group (p<0.01). In comparison with the M group, the TGF-β1 expression was significant lower in the TH and C groups (p<0.01).The TGF-β1 expression on the myocardium after infarction in rats indicates that TGF-β1 has proinflammatory activity. The TGF-β1 participates in the early period of ventricular remodeling and myocardial fibrosis. The ventricular remodeling is closely correlated with myocardial fibrosis. The study shows that the TGF-β1 expression on the myocardium significantly increased in M than TH group after infarction, the TGF-β1 expression was significantly lower (p<0.01) after tongxinluo treatment, which indicates that TGF-β1 plays key role in ventricular remodeling and myocardial fibrosis. Preventing and treating the ventricular remodeling and myocardial fibrosis with tongxinluo is effective. 3 The effects of tongxinluo on TNF-αexpression after infarction in ratTo observe changes of TNF-αprotein expression in the myocardium after infarction in the rats, 80 rats were randomly divided into two groups: sham operation group and coronary artery ligation group. Sham operation group was fed with 0.9 % NaCl for 4 weeks (n=10, after 4 weeks, n=8), and killed after 4 weeks; 70 rats underwent the left descending coronary artery ligation, 38 surviving rats were randomly assigned to one of the following groups: AMI model group (M group, the rats were fed with 0.9 % NaCl for 4 weeks, n=9), high dose Tongxinluo group (TH group, 1.0 g kg-1 d-1, n=10), Captopril group (C group, 15 mg kg-1 d-1, n=10); low dose Tongxinluo group (TL group, 0.05 g kg-1 d-1, n=9). Latter three of all the groups were fed with the medicine for 4 weeks. At the end of the experiment, the rat hearts were fixed and pathologically analyzed. Morphological characteristics were evaluated with HE and Masson staining. The protein expression of TNF-αon the myocardium was detected by immunochemistry and Western blot.Compared to sham operation rats, the TNF-αexpression was enhanced in M group. In comparison with the M group, TNF-αexpression was significantly lower (p<0.01) in the TH group and C group, but TNF-αexpression was not lower in the TL group.TNF-αis not expressed or expressed in low level in normal myocardium, AMI increased expression of TNF-αand resulted in ventricular remodeling triggered by myocardium injury and ischemia. Meanwhile, TNF-αwas closely correlated with left ventricular function. The activation of TNF-αcan affect left ventricular function. The tongxinluo has the inhibitory effects on activation of TNF-α. The left ventricular function was improved after treatment with tongxinluo.Conclusion:1 The tongxinluo reduces the activation of TNF-αand TNF-αexpression. The NF-κB expression in the myocardium of TH group and C group is lower than M group. The phenomenon suggests that NF-κB plays an important role in ventricular remodeling after myocardial infarction. The prevention of ventricular remodeling with tongxinluo after infarction is an effective method .2 Nuclear factor NF-κB is a proinflammatory transcription factor. The proinflammatory cytokines are implicated in the pathogenesis of ventricular remodeling. The NF-κB is activated by myocardium injury and ischemia. NF-κB has some correlation with ventricular remodeling.3 The inhibition of NF-κB expression is based on the anti-oxidative action of tongxinluo.4 The TGF-β1 participates in the early period of ventricular remodeling and myocardial fibrosis. Preventing and treating the myocardial fibrosis with tongxinluo is effective.5 TNF-αhas closely correlation with left ventricular function. The activation of TNF-αaffects left ventricular function. The tongxinluo has the inhibitory effects on activation of TNF-α. The left ventricular function is improved after treatment with tongxinluo.6 The proinflammatory cytokines triggered by myocardial infarction has close correlation with ventricular remodeling.
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