本文選題：厄貝沙坦 + 縫隙連接蛋白　； 參考：《南昌大學(xué)》2016年博士論文

【摘要】：缺血性心臟病引起的心律失常,尤其是室性心律失常(包括室性早搏、室速和室顫)是導(dǎo)致患者猝死的主要原因之一。研究認為細胞內(nèi)存在著大量的氧自由基、鈣超載以及酸性物質(zhì),而室性心律失常是一種多種機制共同作用的過程。通過大量的研究發(fā)現(xiàn),縫隙連接改變和許多病理生理變化有著聯(lián)系,并且縫隙連接的改變和心律失常有著重要的聯(lián)系。學(xué)者們把和心律失常有關(guān)的縫隙連接改變稱為縫隙連接重構(gòu)。縫隙連接是細胞間進行信息通訊以及物質(zhì)交換的重要途徑,對多細胞生命體有著重要的作用。心室肌細胞閏盤內(nèi)縫隙連接的重要連接蛋白為Connexin 43(Cx43),很多研究者通過實驗發(fā)現(xiàn)該物質(zhì)表達與分布的異常與心律失常發(fā)生有關(guān)。因此,研究心肌缺血時Cx43表達是否異常,對缺血后發(fā)生心律失常的作用機制可提供重要的理論依據(jù),為臨床上治療缺血后心律失常起指導(dǎo)作用。第一部分:厄貝沙坦作用后大鼠缺血心肌室性心律失常的發(fā)生及縫隙蛋白Cx43表達目的:探討大鼠心肌缺血時室性心律失常的發(fā)生,并檢測心肌縫隙連接蛋白Cx 43的表達。探討大鼠心肌缺血時厄貝沙坦對心肌Cx43表達及室性心律失常發(fā)生的作用。方法:1、實驗分組:隨機選取40只SD大鼠,分為四組,每組10只,對照組(即假手術(shù)組:只行開胸術(shù),而不造成心肌梗死)、陳舊性心肌梗死組、厄貝沙坦組、陳舊性心肌梗死+厄貝沙坦組。2、大鼠心肌梗死模型的構(gòu)建:大鼠麻醉后,給予呼吸機輔助呼吸,在左心耳與肺動脈圓錐之間距主動脈根部3mm處結(jié)扎冠脈前降支,術(shù)后連續(xù)3天肌肉注射青霉素40萬單位以預(yù)防感染。3、大鼠心梗后室性心律失常的發(fā)生次數(shù):每周2小時監(jiān)測室性心律失常的發(fā)生次數(shù),4周末對比各組大鼠室性心律失常的發(fā)生。4、大鼠心梗后Cx43表達水平的改變:于4周末通過Western blot和免疫組化方法分別檢測正常大鼠心肌與心梗大鼠心肌Cx43蛋白的表達,對比兩者含量變化,闡明心肌缺血與Cx43的關(guān)系。5、ARB類藥物厄貝沙坦(30mg/kg.d)灌胃干預(yù)后觀察對照組大鼠與處理組大鼠,通過連續(xù)心電圖監(jiān)測4周,對比其室性心律失常的發(fā)生次數(shù),闡明厄貝沙坦可否降低室性心律失常的發(fā)生。6、心肌Cx43的改變:陳舊性心肌梗死+厄貝沙坦組大鼠,給予厄貝沙坦灌胃后4周,檢測Cx43表達,闡明ARB類藥物對大鼠心肌Cx43蛋白表達的影響。結(jié)果:1、心梗組室速或室顫發(fā)生率與假手術(shù)組相比明顯增加(P0.05)2、心梗大鼠心肌細胞磷酸化Cx43及總Cx43蛋白表達較假手術(shù)組降低(P0.05);3、對照組大鼠與厄貝沙坦處理組大鼠,通過連續(xù)心電圖監(jiān)測,處理組室性心律失常的發(fā)生次數(shù)明顯少于對照組。4、通過Western Blot方法檢測Cx43蛋白表達情況,相比于陳舊性心肌梗死組,陳舊性心肌梗死+厄貝沙坦組Cx43蛋白表達增加,差異相比較有統(tǒng)計學(xué)意義(P0.05)。結(jié)論:缺血可導(dǎo)致大鼠室性心律失常的發(fā)生明顯增加,并且導(dǎo)致心肌細胞中Cx43的表達水平下降,使用厄貝沙坦后,陳舊性心肌梗死室性心律失常發(fā)生減少,且所致的心室缺血區(qū)Cx43含量減少的程度較陳舊性心肌梗死組減輕。第二部分:厄貝沙坦可逆轉(zhuǎn)特異性低表達縫隙蛋白Cx43而增加的大鼠室性心律失常發(fā)生目的:探討厄貝沙坦可逆轉(zhuǎn)特異性低表達縫隙蛋白Cx43而增加的大鼠室性心律失常發(fā)生。方法:1、降低Cx43表達水平(Cx43基因的沉默作用)2、大鼠分為4組,包括對照組,厄貝沙坦組,注射慢病毒組即低表達組,以及注射慢病毒+厄貝沙坦。慢病毒注射至心臟邊緣區(qū)。病毒注射含量為1*1011病毒數(shù)。造模結(jié)束后1)取各組心臟組織分離心肌細胞檢測心肌細胞的MTT;2)取心臟組織制成切片檢測心肌細胞的凋亡;3)取心臟組織進行Cx43的WB檢測;4)Cx43與室性心律失常:通過連續(xù)心電圖監(jiān)測4周,對比Cx43表達降低大鼠與正常大鼠室性心律失常的發(fā)生次數(shù),闡明Cx43與室性心律失常的關(guān)系。加用厄貝沙坦治療后,觀察室性心律失常發(fā)生。結(jié)果:1.通過Sh RNA慢病毒載體介導(dǎo)使SD大鼠心肌細胞Cx43基因沉默,從而降低Cx43表達水平。2.Cx43表達水平降低的大鼠心肌細胞較正常大鼠心肌細胞存活率,細胞活性降低,凋亡增高(P0.05)3.厄貝沙坦使得特異性低表達Cx43增加的室性心律失常發(fā)生減少。結(jié)論:Cx43基因表達降低的大鼠較正常大鼠室性心律失常的發(fā)生明顯增多。縫隙蛋白數(shù)量與室性心律失常呈負相關(guān)關(guān)系。厄貝沙坦通過Cx43的升高,降低了室性心律失常的發(fā)生。
[Abstract]:Arrhythmia caused by ischemic heart disease, especially ventricular arrhythmias, including ventricular premature beat, ventricular tachycardia, and ventricular fibrillation, is one of the main causes of sudden death. Quantitative studies have found that gap junction changes are associated with many pathophysiological changes, and there is an important link between gap junction changes and arrhythmias. Scholars call the gap junction changes associated with arrhythmias known as gap junction reconstruction. Gap junctions are an important way to communicate information and material exchange among cells. Multi cell life plays an important role. The important connexion protein of gap junction in intercalated intercalary disc of ventricular myocytes is Connexin 43 (Cx43). Many researchers have found that the abnormal expression and distribution of the substance are related to the occurrence of arrhythmia by experiments. Therefore, the abnormalities of Cx43 in myocardial ischemia and arrhythmia after ischemia are studied. The mechanism can provide important theoretical basis for clinical treatment of ischemic arrhythmia. Part 1: the occurrence of ventricular arrhythmia and the expression of crevice protein Cx43 in rat ischemic myocardium after irbesartan: To explore the occurrence of ventricular arrhythmia in myocardial ischemia in rats and to detect the gap connexin Cx 43 in myocardium. To explore the effect of erbesartan on myocardial Cx43 expression and ventricular arrhythmia during myocardial ischemia in rats. Methods: 1, the experimental group: randomly selected 40 SD rats, divided into four groups, 10 in each group, and the control group (sham operation group: only thoracotomy, without myocardial infarction), old myocardial infarction group, irbesartan group, obsolete heart Muscle infarction + erbesartan group.2, rat model of myocardial infarction: after anesthesia, the rats were given ventilator assisted respiration, the anterior descending branch of the coronary artery was ligated from the left atrial appendage to the conus of the pulmonary artery from 3mm to the aorta root. 3 days after the operation, 400 thousand units of penicillin were injected to prevent the infection of.3, and the secondary ventricular arrhythmia occurred in the rats. Number: 2 hours a week, 2 hours of monitoring ventricular arrhythmia occurrence, 4 weekend compared groups of rats with ventricular arrhythmia occurrence.4, rats after myocardial infarction Cx43 expression level changes: the 4 weekend by Western blot and immunohistochemical method to detect the expression of Cx43 protein in myocardium of normal rats and myocardial infarction rats, and compare the changes of the two levels. To elucidate the relationship between myocardial ischemia and Cx43.5, the prognosis of ARB drug erbesartan (30mg/kg.d) was observed in the control group and the treatment group. Through continuous ECG monitoring for 4 weeks, the incidence of ventricular arrhythmias was compared. It was demonstrated that irbesartan could reduce the.6 of ventricular arrhythmia and the change of myocardial Cx43: old myocardium 4 weeks after irbesartan group, the expression of Cx43 was detected by irbesartan, and the effect of ARB on Cx43 protein expression in rat myocardium was examined. Results: 1, the incidence of ventricular tachycardia or ventricular fibrillation in myocardial infarction group was significantly increased (P0.05) compared with that of sham operation group (P0.05) 2, and the expression of Cx43 and total Cx43 protein in myocardial cells of myocardial infarction rats was lower than that of sham operation group. Low (P0.05); 3, the rats in the control group and the erbesartan treatment group were significantly less than the control group.4 by continuous electrocardiogram monitoring. The expression of Cx43 protein was detected by the Western Blot method. Compared to the old myocardial infarction group, the expression of Cx43 protein in the old myocardial infarction + erbesartan group was increased. The difference was statistically significant (P0.05). Conclusion: ischemia can lead to a significant increase in ventricular arrhythmia in rats and a decrease in the level of Cx43 expression in cardiac myocytes. After the use of irbesartan, old myocardial infarct ventricular arrhythmias decrease, and the decrease of Cx43 content in ventricular ischemic areas is older than that of old ones. The second part: the second part: irbesartan can reverse the specific low expression gap protein Cx43 and increase the ventricular arrhythmia in rats. It is discussed that irbesartan can reverse the specific low expression gap protein Cx43 and increase the ventricular arrhythmia in rats. Square method: 1, reduce the expression level of Cx43 (the silence of Cx43 gene) 2, the rats were divided into 4 groups, including the control group, the Irbesartan group, the injection of lentivirus group, the low expression group, and the injection of lentivirus + erbesartan. The injection of lentivirus to the marginal zone of the heart. The injection content of the virus was 1*1011 virus. After the end of the model of the model, the cardiac tissue was divided into MTT of cardiac myocytes by centrifugation muscle cells; 2) the heart tissue was obtained. Apoptosis of cardiac myocytes was detected by slicing; 3) WB detection of Cx43 in cardiac tissue; 4) Cx43 and ventricular arrhythmia: through continuous ECG monitoring for 4 weeks, Cx43 expression decreased the frequency of ventricular arrhythmia in rats and normal rats, clarified the relationship between Cx43 and ventricular arrhythmias. After the treatment with irbesartan, the ventricular heart was observed. Results: 1. the Cx43 gene of SD rat cardiomyocytes was silenced by Sh RNA lentivirus vector, which reduced the survival rate of myocardial cells in rats with lower Cx43 expression level.2.Cx43 expression level, decreased cell activity, and increased apoptosis (P0.05) 3. irbesartan increased the specific low expression of Cx43. Conclusion: the incidence of ventricular arrhythmia in rats with Cx43 gene expression was significantly higher than that of normal rats. The number of gap protein was negatively correlated with ventricular arrhythmia. The increase of erbesartan decreased the occurrence of ventricular arrhythmia by the increase of Cx43.

【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R542.2;R541.7

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