| Objective: 1) Prepare the rat model of heart failure through the induce of isoproterenol, and observe the sequence change occurred of the ventricular myocytes apoptosis (Bcl-2 and Bax protein expression), through which to provide the basis of the effective interventions of drugs. 2) Respectively provide the two drugs the atorvastatin and the pravastatin the heart failure intervention rat, detect the cardiac myocyte apoptosis index and the expression level of the Bcl-2 and the Bax protein to observe the impact to the cardiomyocyte apoptosis related genes Bcl-2 and Bax of the heart failure rat by using different doses and different use of time of the statin drugs; at the same time, detect the TNF-αand the myocardial hydroxyproline content, and discuss the differences of the possible prevention and treatment effect to the heart failure by the pravastatin and the atorvastatin, and further reveal the relationship of the pathogenesis and the pathophysiology of the heart failure and the cardiac myocyte apoptosis, making the prevention and treatment of the chronic heart failure more reasonable and effective. Method: 1) Isoproterenol 300mg/kg, subcutaneous injection, one time repeated per 24 hours and a total of 2 times. Randomly select 8 rats from that on the 1st day, the 3rd day, the 7th day, the 14th day, the 21st day, the 35th day, the 49th day and the 63rd day to carry on the sequence research of establishing the heart failure model, including the detection of the blood flow dynamics and the detection of the cardiac myocyte apoptosis protein Bcl-2 and Bax. 2) Two times of ISO300mg/kg subcutaneous injection, with model construction carried on per 24 hours. Control group subcutaneous injection of normal saline 0.3ml/100g weight. After five weeks, the survival heart failure rats are randomly divided into 5 groups which are given normal saline (0.5ml/100g), atorvastatin 30mg/kg, 10mg/kg (normal saline soluble), pravastatin 120mg/kg and 40mg/kg per day once gastric perfusion; and the control group is given 0.5ml/100g normal saline gastric perfusion. After four weeks of treatment, the echocardiography and the wounded blood testing are given; and at the same time, detect the cardiac muscle cell Bcl-2 and the Bax protein, the expression of the mRNA, the content of the plasma TNF-a, the content of the myocardial hydroxyproline, and calculate the collagen protein content. 3) With 3 days of statin drug pre-intervention to the SD rat, give it isoproterenol 300mg/kg and subcutaneous injection. And the haemodynamics should be detected respectively after giving the injection by 6 hours and 72 hours, and detect the Bcl-2 and the Bax apoptosis protein expression. Result: 1) After ISO 300mg/kg rat abdominal injection, the weight increasing of the rat of the ISO group is significantly slower than that of the control group. The heart specimen shows that the heart surface of the ISO group is bleak, and the color is dark purple; and along with the prolonging of the cycle, the heart obviously expands and the pulse is weak; the rat mortality rate is 25.6 percent; after that the rat cardiomyocytes is injured by the isoproterenol, the average aortic pressure (MAP) is of the gradually downward trend after the model construction, and the maximum rate of rise (+ dp / dtmax) in the left ventricular is significantly decreased (P<0.05) after seven weeks; and the maximum rate of decline (-dp/dtmax) in the left ventricular is significantly increased (P<0.05) and the EF value and the FS value are significantly decreased (P < 0.05); the cardiac function is significantly impaired (P < 0.05), and the left ventricular merit index (LVWI) is significantly increased (P<0.05) than that of the control group, and it presented that the isoproterenol induced rat heart failure model is established. 2) The heart failure rat is interfered by the statin drugs, and after the intervention of the atorvastatin, the EF, FS and dp / dtmax are significantly increased, and the -dp/dtmax is decreased significantly, the LVESD and the left ventricular merit index are decreased significantly, and the content of the myocardial hydroxyproline is decreased; compared the indicators of the two groups, the improving effect of the left ventricular remodeling and cardiac function of the atorvastatin intervention 30mg/kg group may be better. At the same time, the EF, FS and dp / dtmax of the pravastatin 120mg/kg group and the 40mg/kg group are increased more than that of the ISO group, and the -dp/dtmax, the LVESD, the left ventricular merit index and the myocardial hydroxyproline content are also decreased, but the difference has no statistical significance. The small doses application of the atorvastatin can inhibit the TNF-α, improve the inflammatory response state and is conducive to slow down the process of heart failure. The statin drugs can inhibit the expression of the myocardial Bax protein, reduce the Bax/Bcl-2 high ratio imbalance in the myocardial cells induced by the increasing of the catecholamine and make it be balance and inhibit the cardiomyocyte apoptosis. 3) After the statin drugs pre-intervention, the isoproterenol injection is given; and after 6 hours, the left ventricular merit index is increased significantly (P<0.05), the heart rate is fasted significantly (P<0.05), and the aortic mean pressure is decreased significantly (P<0.05); the +dp / dtmax and the -dp / dtmax are both lower than that of the control group (P<0.05), and the Bax expression is increased significantly (P<0.05). After 72 hours, the isoproterenol injection is given, and the weights of the groups are reduced significantly (P<0.01) than that of before, and the heart rate, aortic mean pressure and the±dp / dtmax are increased than that after 6 hours, but the difference has no statistical significance (p> 0.05). The left ventricular merit indexes of the ISO group, the pravastatin 120mg/kg and the 40mg/kg group are increased significantly (P<0.05); and after the isoproterenol injection, the left ventricular merit indexes are all higher than that of the control group (P<0.05). The bcl-2 and bax expression levels are further increased (P<0.05); the bax/bcl-2 ratio in the pravastatin 120mg/kg, 40mg/kg group and atorvastatin 10mg/kg group are significantly higher (P<0.05) than that of the control group, but the increasing of that of the atorvastatin 30mg/kg group is not obvious (P> 0.05). Conclusion: 1) 300mg/kg subcutaneous isoproterenol injection, the interval is 24h, altogether 2 times, and the rat heart failure model establishing can be induced after 7 weeks. 2) The Bcl-2 and Bax sequences change during the isoproterenol-induced rat heart failure process: the Bcl-2 protein expression is increased gradually, and it is decreased gradually after it reached the peak; and the Bax protein expression is also markedly increased, and the time it reached the peak is slightly later than that of the Bcl-2 and the lowering is slow thereafter. The Bax/Bcl-2 ratio is imbalanced at a high level, which promotes the occurrence of apoptosis, and increases the ventricular remodeling and promotes the occurrence of heart failure. 3) Use the atorvastatin 30mg/kg and 10mg/kg and pravastatin 120mg/kg and 40mg/kg to respectively interfere the heart failure rat, the atorvastatin treatment can significantly improve the left ventricular remodeling and cardiac function. And use a high-dose 30mg/kg group to improve the left ventricular remodeling and cardiac function may get a better effect. 4) Through inhibiting the myocardial collagen generating, the statin drugs reduce the interstitial fibrosis, inhibit the TNF-α, improve the inflammatory response state, inhibit the myocardial Bax protein expression, reduce the Bax/Bcl-2 high ratio imbalance in the myocardial cells induced by the increasing of the catecholamine and make it be balance and inhibit the cardiomyocyte apoptosis. 5) It has the significant significance on the aspect of the left ventricular remodeling by using the atorvastatin pre-intervention to the isopropyl injured rat myocardium, and the using of the atorvastatin in the early stage may be beneficial to the myocardium injured. Its protection function to the acute myocardial injury may be realized through promoting the Bcl-2 expression to make the bax / Bcl-2 ratio be balanced and through which to influence the cardiomyocyte apoptosis.
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