本文選題：轉(zhuǎn)化生長(zhǎng)因子-β1-Smad3通路 + 谷氨酰胺　； 參考：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文

【摘要】：背景：轉(zhuǎn)化生長(zhǎng)因子-β1 (transforming growth factor-β1, TGF-β1)-Smad3通路的激活可以加重心肌缺血再灌注損傷。糖尿病患者的心肌組織中TGF-β1-Smad3通路被明顯地激活,這極有可能成為糖尿病患者經(jīng)歷心肌缺血再灌注損傷預(yù)后較差的重要原因之一。我們前期的體外實(shí)驗(yàn)已經(jīng)證明了谷氨酰胺可以減輕高糖聯(lián)合缺氧復(fù)氧所導(dǎo)致的心肌細(xì)胞損傷。本次實(shí)驗(yàn)的研究目的是進(jìn)一步深入研究谷氨酰胺能否可以通過抑制TGF-β1-Smad3這條通路,發(fā)揮抗糖尿病心肌缺血再灌注損傷的作用。方法：體外實(shí)驗(yàn)里,我們將H9c2大鼠心肌細(xì)胞置于33mM的高糖環(huán)境下培養(yǎng),然后進(jìn)行缺氧復(fù)氧和對(duì)照處理。首先,給予婧GF-β1受體抑制劑SB431542和Smad3的特異性抑制劑SIS3對(duì)Smad3通路進(jìn)行抑制,觀察細(xì)胞損傷變化。其次,我們使用不同濃度的谷氨酰胺進(jìn)行干預(yù)治療觀察對(duì)心肌細(xì)胞Smad3通路的影響。最后,我們又應(yīng)用人重組的TGF-β1激活Smad3通路來(lái)進(jìn)行驗(yàn)證。體內(nèi)實(shí)驗(yàn)中,我們首先建立糖尿病大鼠模型；然后對(duì)正常大鼠和糖尿病大鼠分別給予生理鹽水或谷氨酰胺溶液灌胃處理；最后再進(jìn)行心肌缺血再灌注損傷的干預(yù)。我們應(yīng)用Western blotting技術(shù)檢測(cè)了H9c2心肌細(xì)胞和大鼠心肌組織中TGF-β1,總Smad3,磷酸化Smad3和活化的caspase-3的表達(dá)水平。應(yīng)用TUNEL法檢測(cè)了心肌細(xì)胞和心肌組織中的細(xì)胞凋亡率。我們也檢測(cè)了大鼠心肌梗死面積和電鏡下心肌微觀結(jié)構(gòu)的變化以及大鼠的相關(guān)血流動(dòng)力學(xué)指標(biāo)參數(shù)的變化。結(jié)果：研究發(fā)現(xiàn)：在體外實(shí)驗(yàn)中,高糖+缺氧復(fù)氧組中的H9c2細(xì)胞的凋亡率最高,同樣該組的TGF-β1-Smad3通路被激活的也最明顯。TGF-β1受體抑制劑SB431542和Smad3的特異性抑制劑SIS3均可以明顯下調(diào)Smad3的磷酸化水平,并能夠有效減輕對(duì)心肌細(xì)胞的高糖+缺氧復(fù)氧損傷。同樣地,補(bǔ)充谷氨酰胺后,細(xì)胞的凋亡水平下降了,并且TGF-β1-Smad3通路的激活也被抑制了。然而,當(dāng)外源給予人重組TGF-β1后,谷氨酰胺的保護(hù)作用則削弱了,心肌細(xì)胞凋亡水平明顯增加。在體內(nèi)實(shí)驗(yàn)中,非谷氨酰胺治療組的糖尿病大鼠經(jīng)歷心肌缺血再灌注后心臟損傷最嚴(yán)重。對(duì)糖尿病大鼠進(jìn)行補(bǔ)充谷氨酰胺治療可以明顯改善心肌缺血再灌注后的血流動(dòng)力學(xué)指標(biāo),減少心肌細(xì)胞凋亡、心肌微觀結(jié)構(gòu)損害與心肌梗死面積,同時(shí)也抑制了心肌組織中TGF-β1-Smad3通路的激活。結(jié)論：因此,我們得出以下結(jié)論：TGF-β1-Smad3通路的激活可以加重糖尿病心肌缺血再灌注損傷;補(bǔ)充谷氨酰胺可以部分通過抑制TGF-β1-Smad3通路減輕了糖尿病心肌缺血再灌注損傷。背景：在論文第一部分的研究中,我們采用了SD大鼠建立了心肌缺血模型。這種小型嚙齒類動(dòng)物的心臟大小及結(jié)構(gòu)與人類心臟相差較大,在一些實(shí)驗(yàn)應(yīng)用方面受到限制。而某些大型動(dòng)物則體現(xiàn)出獨(dú)特的優(yōu)勢(shì)。如比格犬,它具有與人類相似的心臟結(jié)構(gòu)及病理生理反應(yīng),且循環(huán)系統(tǒng)發(fā)達(dá),更適合于心血管疾病的研究。比格犬遺傳性能穩(wěn)定且優(yōu)良,也為實(shí)驗(yàn)的均一性也提供了保障。目前缺少一種與臨床狀態(tài)相近的,可以評(píng)價(jià)溶栓療效的心肌缺血?jiǎng)游锬Ｐ�。所以在論文第二部分�?shí)驗(yàn)中,我們首先分析了臨床中冠狀動(dòng)脈血栓的成分后,然后利用微創(chuàng)介入技術(shù)在冠狀動(dòng)脈內(nèi)注入自體栓子的方法研發(fā)了一種能夠評(píng)價(jià)溶栓藥物療效的比格犬心肌缺血模型,也為后續(xù)探討溶栓后的缺血再灌注損傷相關(guān)機(jī)制奠定了實(shí)驗(yàn)基礎(chǔ)。方法：我們選取了18只比格犬進(jìn)行了此次實(shí)驗(yàn),一共分為3組：紅色血栓組(n=6只),白色血栓組(n=6只)和白色血栓+rt-PA溶栓再灌注組(n=6只)。自制的自體血栓被注入到冠狀動(dòng)脈前降支的中遠(yuǎn)段。通過心電圖和心電監(jiān)護(hù)儀監(jiān)測(cè)冠狀動(dòng)脈栓塞及溶栓再灌注過程。應(yīng)用冠狀動(dòng)脈造影確定血栓在體狀態(tài)。應(yīng)用HE染色和電鏡技術(shù)對(duì)不同血栓成分進(jìn)行分析。應(yīng)用2,3,5-氯化三苯基四氮唑(TTC)染色計(jì)算心肌梗死面積。結(jié)果:經(jīng)過HE染色和掃描電鏡分析發(fā)現(xiàn),紅色血栓具備松散的網(wǎng)狀結(jié)構(gòu)特點(diǎn),網(wǎng)眼中充滿紅細(xì)胞；而白色血栓的結(jié)構(gòu)較為緊密,它主要有密集的纖維蛋白構(gòu)成。冠狀動(dòng)脈造影顯示,當(dāng)冠狀動(dòng)脈栓塞3小時(shí)后,紅色血栓組的再通率(自溶率)為2/6,而白色血栓組再通率為0/6。并且紅色血栓組再通的2例均出現(xiàn)了心律失常,心電圖表現(xiàn)出升高的ST段回落和原理高聳的T波出現(xiàn)降低,上述這些改變沒有發(fā)生于白色血栓組中。我們又將另外的6例白色血栓栓塞的比格犬(白色血栓+rt-PA組)進(jìn)行阿替普酶(rt-PA)溶栓治療。冠狀動(dòng)脈造影發(fā)現(xiàn)給予rt-PA溶栓后2小時(shí),有5例出現(xiàn)了冠狀動(dòng)脈再通,再通時(shí)間為43.2±7.4分鐘。白色血栓對(duì)照組未發(fā)現(xiàn)血管再通跡象。TTC染色顯示溶栓組的心肌梗死面積明顯小于非溶栓組(白色血栓組)的心肌梗死面積。結(jié)論：我們自制的白色血栓動(dòng)物模型在實(shí)驗(yàn)方法操作上更加便利,均一性好,穩(wěn)定性和成功率高。這項(xiàng)研究最主要的創(chuàng)新點(diǎn)在于我們利用的栓子與臨床溶栓窗口內(nèi)的冠狀動(dòng)脈血栓成分相似,都是主要由纖維蛋白構(gòu)成,所以該模型可以較好地用來(lái)評(píng)價(jià)治療ST段抬高型心肌梗死的溶栓新藥療效；該模型能夠最大限度地模擬臨床溶栓后心肌缺血再灌注損傷的狀態(tài),因此也可以用來(lái)探討溶栓后心肌缺血再灌注損傷的病理變化及機(jī)制。
[Abstract]:Background: activation of the -Smad3 pathway of transforming growth factor - beta 1 (transforming growth factor- beta 1, TGF- beta 1) can aggravate myocardial ischemia reperfusion injury. The TGF- beta 1-Smad3 pathway in the myocardium of diabetic patients is obviously activated, which may be an important factor in the poor prognosis of diabetic patients undergoing myocardial ischemia reperfusion injury. One of our previous experiments has demonstrated that glutamine can reduce the myocardial damage caused by high glucose combined with hypoxia reoxygenation. The purpose of this study is to further investigate whether glutamine can play an anti diabetic myocardial ischemia-reperfusion injury by inhibiting the TGF- beta 1-Smad3 pathway. Methods: in the experiment in vitro, we cultured the H9c2 rat cardiomyocytes under the high glucose environment of 33mM, and then carried out anoxic reoxygenation and control treatment. First, the Smad3 pathway was suppressed by the specific inhibitor SIS3 of the GF- beta 1 receptor inhibitor SB431542 and Smad3, and the changes in the cell damage were observed. Secondly, we used different concentrations of the valley. The effects of aminamides on the Smad3 pathway of cardiac myocytes were observed. Finally, we used recombinant human TGF- beta 1 to activate the Smad3 pathway to verify. In vivo, we first established the diabetic rat model, and then treated normal rats and diabetic rats with saline or glutamine solution respectively. Finally, the intervention of myocardial ischemia reperfusion injury. We detected the expression level of TGF- beta 1, total Smad3, phosphorylated Smad3 and activated caspase-3 in H9c2 myocardial cells and rat myocardium by using Western blotting technique. We detected the apoptosis rate in cardiac myocytes and myocardium by TUNEL method. We also detected the large amount of apoptosis in cardiac myocytes and myocardium. Changes in myocardial infarction area and ultrastructure of myocardium under electron microscope and changes in the parameters of hemodynamic indexes of rats. Results: the results were as follows: in the experiment, the apoptosis rate of H9c2 cells in the high glucose and hypoxia reoxygenation group was the highest, and the TGF- beta 1-Smad3 pathway was also the most obvious.TGF- beta 1 receptor inhibitor in this group The specific inhibitor SIS3 of SB431542 and Smad3 can obviously downregulate the phosphorylation level of Smad3 and effectively reduce the high glucose + hypoxia reoxygenation damage to cardiac myocytes. Similarly, after supplementation of glutamine, the apoptosis level of the cells decreased and the activation of the TGF- beta 1-Smad3 pathway was inhibited. However, when exogenous TGF- was given to human recombinant TGF- After beta 1, the protective effect of glutamine was weakened and the level of cardiomyocyte apoptosis increased significantly. In the experiment of the non glutamine treatment group, the diabetic rats underwent the most severe cardiac injury after myocardial ischemia reperfusion. Mechanical indexes, which reduce myocardial apoptosis, myocardial microstructure damage and myocardial infarction area, also inhibit the activation of TGF- beta 1-Smad3 pathway in myocardial tissue. Conclusion: therefore, we conclude that the activation of TGF- beta 1-Smad3 pathway can aggravate the injury of myocardial ischemia reperfusion injury in diabetic myocardium; supplemental glutamine can be used in partial passage. Inhibition of TGF- beta 1-Smad3 pathway alleviates myocardial ischemia and reperfusion injury in diabetic myocardium. Background: in the first part of the paper, we established a model of myocardial ischemia in SD rats. The size and structure of this small rodent are different from that of the human heart, and some of the experimental applications are limited. The Beagle dog, such as the Beagle dog, has a similar heart structure and a pathophysiological reaction that is similar to human, and has a developed circulation system that is more suitable for the study of cardiovascular disease. The genetic performance of the Beagle dog is stable and excellent. It also provides protection for the homogenization of the experiment. In the second part of the paper, we first analyzed the components of coronary artery thrombosis in the clinic, and then developed a beagle myocardial ischemia model that can evaluate the therapeutic effect of thrombolytic drugs by injecting autologous embolus into the coronary artery by minimally invasive interventional technique. The experimental basis was laid for subsequent study of the mechanism of ischemic reperfusion injury after thrombolysis. Methods: We selected 18 beagle dogs, divided into 3 groups: the red thrombus group (n=6), the white thrombus group (n=6) and the white thrombus +rt-PA thrombolytic reperfusion group (n=6 only). The self-made autologous thrombus was injected into the coronary artery. The middle and far segment of the anterior descending branch of the pulse. Coronary artery embolization and thrombolytic reperfusion were monitored by electrocardiogram and electrocardiogram monitor. Coronary angiography was used to determine thrombus in body state. HE staining and electron microscopy were used to analyze different thrombus components. The area of myocardial infarction was calculated by 2,3,5- chlorination of three phenyl tetrazolium (TTC). Results: After HE staining and scanning electron microscopy, red thrombus had a loose reticular structure, and the eyes were filled with red blood cells, and the white thrombus had a tight structure. It was mainly composed of dense fibrin. Coronary angiography showed that the repass rate of the red thrombus group (autolysis) was 2/6 after 3 hours of coronary artery embolism. The repass rate of the white thrombus group was 0/6. and 2 cases of the red thrombus group had arrhythmia. The electrocardiogram showed an elevated ST segment and a decrease in the principle of the high principle T wave. These changes did not occur in the white thrombus group. We also performed the other 6 cases of white thrombus in the Beagle (white thrombus +rt-PA group). Rt-PA thrombolytic therapy. Coronary angiography was found 2 hours after rt-PA thrombolytic thrombolysis. Coronary repassage was found in 5 cases and repass time was 43.2 + 7.4 minutes. The white thrombus control group did not find the vascular repassage sign.TTC staining showed that the infarct area of the thrombolytic group was significantly smaller than that of the non thrombolytic group (white thrombus group). Death area. Conclusion: our homemade white thrombus animal model is more convenient, homogeneous, stable and successful. The main innovation of this study is that the embolus used in this study are similar to the components of coronary artery thrombus within the clinical thrombolytic window, which are mainly made up of fibrin, so this model is a model. The model can be used to evaluate the efficacy of a new thrombolytic drug for the treatment of ST segment elevation myocardial infarction. This model can simulate the state of myocardial ischemia reperfusion injury to the maximum extent, and therefore can also be used to explore the pathological changes and mechanisms of myocardial ischemia reperfusion injury after thrombolytic therapy.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R542.2;R-332;R587.2

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9 吳志明;董麗莉;樊冰;潘翠珍;舒先紅;;斑點(diǎn)追蹤顯像技術(shù)評(píng)價(jià)心肌缺血再灌注對(duì)心肌扭轉(zhuǎn)影響的實(shí)驗(yàn)研究[A];第十屆全國(guó)超聲心動(dòng)圖學(xué)術(shù)會(huì)議論文[C];2010年

10 袁肇凱;黃獻(xiàn)平;曹金枝;胡志希;簡(jiǎn)亞平;;心肌缺血再灌注損傷大鼠冠狀微循環(huán)改變的實(shí)驗(yàn)研究[A];中國(guó)微循環(huán)學(xué)會(huì)第五屆中國(guó)微循環(huán)學(xué)術(shù)大會(huì)論文摘要匯編[C];2004年

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