去腎交感神經(jīng)術(shù)對(duì)心衰犬心功能及凋亡相關(guān)基因表達(dá)的影響
發(fā)布時(shí)間：2018-08-08 12:07
【摘要】：背景心肌細(xì)胞凋亡作為心肌梗死后心力衰竭(MI-HF)的主要發(fā)病機(jī)制之一,在HF的發(fā)生發(fā)展及進(jìn)程中至關(guān)重要。MI后缺血缺氧、氧化應(yīng)激、炎癥介質(zhì)的產(chǎn)生及異常的神經(jīng)體液機(jī)制等局部惡劣微環(huán)境的作用下,細(xì)胞發(fā)生凋亡,可導(dǎo)致心肌有效收縮單位喪失、膠原纖維沉積,促進(jìn)了心室重構(gòu)及心室功能的惡化進(jìn)展。心肌細(xì)胞的丟失與心功能不可逆性下降相關(guān),因此抑制心梗后心肌凋亡有關(guān)的不良刺激因素,進(jìn)而延緩心臟重構(gòu)及心室擴(kuò)張的進(jìn)程,改善并提高心功能,對(duì)于心衰患者的治療具備臨床指導(dǎo)意義。目前,去腎交感神經(jīng)術(shù)(RDN)正成為治療心衰的熱點(diǎn),已有研究顯示RDN可以降低心室起搏所致房顫動(dòng)物模型的心肌細(xì)胞凋亡現(xiàn)象進(jìn)而改善心功能,但對(duì)于RDN是否可以調(diào)節(jié)MI-HF的細(xì)胞凋亡現(xiàn)象及其相關(guān)機(jī)制尚不明確。目的本實(shí)驗(yàn)旨在探討RDN對(duì)MI-HF犬心功能及細(xì)胞凋亡相關(guān)基因表達(dá)的影響。方法將18只健康雜種犬隨機(jī)分為正常組、模型組及治療組,其中模型組及治療組采用無(wú)水酒精栓塞法制作心梗后心衰模型。治療組犬在心衰造模成功后行雙側(cè)腎動(dòng)脈消融治療,模型組犬行腎動(dòng)脈造影。測(cè)量基線、腎動(dòng)脈消融前及消融術(shù)后4周心功能參數(shù);ELISA法檢測(cè)血清NT-Pro BNP水平;心肌纖維化水平應(yīng)用Masson染色法進(jìn)行觀察評(píng)估;通過(guò)TUNEL法觀察心肌細(xì)胞凋亡狀況并計(jì)算凋亡指數(shù)(AI),RT-PCR及WB法檢測(cè)心肌凋亡指標(biāo)Bcl-2、Bax、Caspase-3及GRP78相對(duì)表達(dá)量;腎動(dòng)脈HE染色評(píng)估RDN術(shù)去神經(jīng)化的有效性;檢測(cè)血清肌酐水平,以評(píng)估手術(shù)操作安全性。結(jié)果1、基線時(shí)三組實(shí)驗(yàn)犬在體重、HR、LVEDD、LVESD、LVEF、LVEDP及LVSP兩兩比較差異均無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。腎動(dòng)脈消融前,與正常犬比較,心衰犬(模型組+治療組)LVEDD、LVESD及LVEDP增加(P0.05),而LVEF、LVSP下降(P0.05);模型組與治療組相比,各心功能參數(shù)均無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。消融術(shù)后4周,與模型組比較,經(jīng)RDN治療后LVEDD、LVESD及LVEDP降低(P0.05),LVEF及LVSP增加(P0.05),而模型組+治療組犬較正常組犬LVEDD、LVESD及LVEDP增加(P0.05),LVEF降低(P0.05),模型組LVSP較正常組降低(P0.05),而治療組犬LVSP較術(shù)前稍有升高,與正常組無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。2、基線時(shí)三組實(shí)驗(yàn)犬血清NT-Pro BNP水平無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。腎動(dòng)脈消融前,心衰犬較正常組犬血清NT-Pro BNP值增加(P0.05);模型組與治療組相比,NT-Pro BNP水平無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。消融后4周,與模型組比較,經(jīng)RDN治療后血清NT-Pro BNP值降低(P0.05);而模型組+治療組犬較正常組犬NT-Pro BNP水平增加(P0.05)。3、消融后4周,與正常組犬比較,心衰犬心肌組織Bcl-2 m RNA及蛋白含量表達(dá)下降(P0.05),Bax、caspase-3、GRP78 m RNA及蛋白表達(dá)與心肌凋亡指數(shù)升高(P0.05);與模型組犬相比,經(jīng)RDN治療后心肌Bcl-2 m RNA及蛋白表達(dá)上調(diào)(P0.05),Bax、caspase-3、GRP78 m RNA及蛋白表達(dá)與凋亡指數(shù)下調(diào)(P0.05)。4、消融后4周,HE染色顯示RDN術(shù)后腎動(dòng)脈血管外膜神經(jīng)纖維軸突缺失破化。5、基線及腎動(dòng)脈消融術(shù)前,三組實(shí)驗(yàn)犬血清肌酐值無(wú)統(tǒng)計(jì)學(xué)差異(P0.05);消融后4周,與正常組比較,模型組犬血清肌酐值升高(P0.05),而治療組肌酐值變化無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。結(jié)論RDN可改善心肌梗死后心衰犬的心功能,我們推測(cè)可能與RDN上調(diào)抗凋亡基因Bcl-2的表達(dá),下調(diào)抑凋亡基因Bax、Caspase-3及GRP78表達(dá)水平,進(jìn)而降低細(xì)胞凋亡程度有關(guān)。
[Abstract]:Background cardiac myocyte apoptosis is one of the main pathogenesis of heart failure (MI-HF) after myocardial infarction. In the development and process of HF, the cell apoptosis is induced by ischemia and hypoxia, oxidative stress, the production of inflammatory mediators and abnormal neurohumoral mechanism, which can lead to the effective myocardial harvest of the myocardium. Loss of units and deposition of collagen fibers contribute to the deterioration of ventricular remodeling and ventricular function. The loss of cardiac myocytes is associated with a decline in cardiac function irreversibility, thus inhibiting the adverse stimulus related to myocardial apoptosis after myocardial infarction, further delaying the process of cardiac remodeling and ventricular dilatation, and improving cardiac function in patients with heart failure. At present, RDN is becoming a hot spot in the treatment of heart failure. Research has shown that RDN can reduce cardiac apoptosis in the animal model of atrial fibrillation induced by ventricular pacing and then improve cardiac function, but it is still unclear whether RDN can regulate the apoptosis of MI-HF and its related mechanisms. The purpose of this experiment was to investigate the effect of RDN on the cardiac function and the expression of apoptosis related genes in MI-HF dogs. Methods 18 healthy hybrid dogs were randomly divided into normal group, model group and treatment group. The model group and the treatment group were used to make heart failure model after myocardial infarction. Renal artery ablation was used in the treatment of renal artery. The heart function parameters were measured at baseline, 4 weeks after renal artery ablation and 4 weeks after ablation. The level of serum NT-Pro BNP was measured and the level of myocardial fibrosis was evaluated by Masson staining. The apoptosis of myocardial cells was observed by TUNEL, and the apoptosis index (AI), RT-PCR and WB were calculated. The relative expressions of Bcl-2, Bax, Caspase-3 and GRP78 were detected by the method of myocardial apoptosis, and the renal artery HE staining was used to evaluate the effectiveness of RDN neurosurgery, and the level of serum creatinine was detected to evaluate the safety of operation. Results 1, there were no significant differences in weight, HR, LVEDD, LVESD, LVEF, LVEDP, and LVSP 22 in the three groups of experimental dogs at baseline. Before renal artery ablation, compared with normal dogs, LVEDD, LVESD and LVEDP increased (P0.05) in heart failure dogs (model group + treatment group), and LVEF, LVSP decreased (P0.05). Compared with the treatment group, there was no statistical difference between the model group and the treatment group (P0.05). Compared with the model group, LVEDD, LVESD and LVEDP decreased after 4 weeks of RDN treatment. In model group + treatment group, LVEDD, LVESD and LVEDP increased (P0.05), LVEF decreased (P0.05), LVSP in model group was lower than that of normal group (P0.05), but the LVSP in the treatment group was slightly higher than that before the operation. There was no statistical difference between the treatment group and the normal group (P0.05).2. There was no statistical difference between the three groups of dogs. Before the renal artery ablation, the NT-Pro BNP value of heart failure dog was increased (P0.05) than that of the normal group. Compared with the treatment group, the level of NT-Pro BNP was not statistically significant (P0.05). After 4 weeks of ablation, the serum NT-Pro BNP value of the model group decreased after RDN treatment (P0.05), while the model group + treatment group was more than the normal group. 4 weeks after ablation, the expression of Bcl-2 m RNA and protein content in heart failure dogs decreased (P0.05), Bax, Caspase-3, GRP78 m RNA and protein expression and the increase of myocardial apoptosis index (P0.05). Down regulation of apoptosis index (P0.05).4, 4 weeks after ablation, HE staining showed that the renal artery epicardial nerve fiber axonal deletion of the renal artery was.5 after RDN. Before the baseline and the renal artery ablation, the serum creatinine value of the three experimental dogs was not statistically different (P0.05). After 4 weeks, the serum creatinine value of the model group was elevated (P0.05), and the treatment group was compared with the normal group (P0.05). There is no significant difference in creatinine value (P0.05). Conclusion RDN can improve cardiac function of heart failure dogs after myocardial infarction. We speculate that RDN may up regulate the expression of anti apoptotic gene Bcl-2, down regulation of apoptosis gene Bax, Caspase-3 and GRP78 expression level, and then decrease the degree of apoptosis.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R541.6
本文編號(hào)：2171739
[Abstract]:Background cardiac myocyte apoptosis is one of the main pathogenesis of heart failure (MI-HF) after myocardial infarction. In the development and process of HF, the cell apoptosis is induced by ischemia and hypoxia, oxidative stress, the production of inflammatory mediators and abnormal neurohumoral mechanism, which can lead to the effective myocardial harvest of the myocardium. Loss of units and deposition of collagen fibers contribute to the deterioration of ventricular remodeling and ventricular function. The loss of cardiac myocytes is associated with a decline in cardiac function irreversibility, thus inhibiting the adverse stimulus related to myocardial apoptosis after myocardial infarction, further delaying the process of cardiac remodeling and ventricular dilatation, and improving cardiac function in patients with heart failure. At present, RDN is becoming a hot spot in the treatment of heart failure. Research has shown that RDN can reduce cardiac apoptosis in the animal model of atrial fibrillation induced by ventricular pacing and then improve cardiac function, but it is still unclear whether RDN can regulate the apoptosis of MI-HF and its related mechanisms. The purpose of this experiment was to investigate the effect of RDN on the cardiac function and the expression of apoptosis related genes in MI-HF dogs. Methods 18 healthy hybrid dogs were randomly divided into normal group, model group and treatment group. The model group and the treatment group were used to make heart failure model after myocardial infarction. Renal artery ablation was used in the treatment of renal artery. The heart function parameters were measured at baseline, 4 weeks after renal artery ablation and 4 weeks after ablation. The level of serum NT-Pro BNP was measured and the level of myocardial fibrosis was evaluated by Masson staining. The apoptosis of myocardial cells was observed by TUNEL, and the apoptosis index (AI), RT-PCR and WB were calculated. The relative expressions of Bcl-2, Bax, Caspase-3 and GRP78 were detected by the method of myocardial apoptosis, and the renal artery HE staining was used to evaluate the effectiveness of RDN neurosurgery, and the level of serum creatinine was detected to evaluate the safety of operation. Results 1, there were no significant differences in weight, HR, LVEDD, LVESD, LVEF, LVEDP, and LVSP 22 in the three groups of experimental dogs at baseline. Before renal artery ablation, compared with normal dogs, LVEDD, LVESD and LVEDP increased (P0.05) in heart failure dogs (model group + treatment group), and LVEF, LVSP decreased (P0.05). Compared with the treatment group, there was no statistical difference between the model group and the treatment group (P0.05). Compared with the model group, LVEDD, LVESD and LVEDP decreased after 4 weeks of RDN treatment. In model group + treatment group, LVEDD, LVESD and LVEDP increased (P0.05), LVEF decreased (P0.05), LVSP in model group was lower than that of normal group (P0.05), but the LVSP in the treatment group was slightly higher than that before the operation. There was no statistical difference between the treatment group and the normal group (P0.05).2. There was no statistical difference between the three groups of dogs. Before the renal artery ablation, the NT-Pro BNP value of heart failure dog was increased (P0.05) than that of the normal group. Compared with the treatment group, the level of NT-Pro BNP was not statistically significant (P0.05). After 4 weeks of ablation, the serum NT-Pro BNP value of the model group decreased after RDN treatment (P0.05), while the model group + treatment group was more than the normal group. 4 weeks after ablation, the expression of Bcl-2 m RNA and protein content in heart failure dogs decreased (P0.05), Bax, Caspase-3, GRP78 m RNA and protein expression and the increase of myocardial apoptosis index (P0.05). Down regulation of apoptosis index (P0.05).4, 4 weeks after ablation, HE staining showed that the renal artery epicardial nerve fiber axonal deletion of the renal artery was.5 after RDN. Before the baseline and the renal artery ablation, the serum creatinine value of the three experimental dogs was not statistically different (P0.05). After 4 weeks, the serum creatinine value of the model group was elevated (P0.05), and the treatment group was compared with the normal group (P0.05). There is no significant difference in creatinine value (P0.05). Conclusion RDN can improve cardiac function of heart failure dogs after myocardial infarction. We speculate that RDN may up regulate the expression of anti apoptotic gene Bcl-2, down regulation of apoptosis gene Bax, Caspase-3 and GRP78 expression level, and then decrease the degree of apoptosis.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R541.6
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