本文選題：心肌缺血再灌注損傷 + microNAs�。� 參考：《昆明醫(yī)科大學(xué)》2016年博士論文

【摘要】：研究背景目前,開(kāi)胸手術(shù)已被廣泛用于治療各種類(lèi)型的心臟疾病,體外循環(huán)是開(kāi)胸心臟手術(shù)中至關(guān)重要的手段。盡管如此,一些研究揭示了這種手術(shù)本身能夠引起人體多種器官的損傷,其中多數(shù)伴隨著組織器官的缺血再灌注損傷。因此,研究缺血再灌注損傷的機(jī)制,嘗試規(guī)避或減弱這一臨床問(wèn)題將為患者帶來(lái)益處。miRNAs是短片段單鏈非編碼RNAs,它能夠靶向mRNAs進(jìn)行轉(zhuǎn)錄后調(diào)控。不斷積累的研究表明了miRNAs在缺血再灌注損傷的發(fā)展過(guò)程中扮演重要角色,其可能成為治療心肌缺血再灌注損傷的潛在靶點(diǎn)。目的：本研究通過(guò)嘗試了解體外循環(huán)的心臟手術(shù)過(guò)程中一些與心肌有關(guān)的miRNAs變化,并對(duì)miR-208a這一關(guān)鍵miRNA進(jìn)行深入研究,利用大鼠缺血再灌注模型檢測(cè)miR-208a在缺血再灌注損傷中的作用。以期為缺血再灌注的早期診斷、防治提供理論依據(jù),為未來(lái)的分子治療提供潛在靶點(diǎn)。方法：1, qRT-PCR檢測(cè)15例風(fēng)心病患者體外循環(huán)的開(kāi)胸手術(shù)過(guò)程中miR-1/21/208a/499分別在四個(gè)時(shí)間點(diǎn)的表達(dá)水平(術(shù)前、主動(dòng)脈阻斷45 mmin后、再灌注60mmin后、術(shù)后24h)；檢測(cè)傳統(tǒng)生理生化指標(biāo)肌酸激酶同工酶(CK-MB)和肌鈣蛋白1(cTnI)的水平；通過(guò)統(tǒng)計(jì)學(xué)分析檢測(cè)它們之間的相關(guān)性。2,構(gòu)建大鼠缺血再灌注模型,將Wistar大鼠隨機(jī)分為假手術(shù)組(Sham)和缺血再灌注組(I/R),Sham組大鼠僅開(kāi)胸,I/R組開(kāi)胸結(jié)扎冠狀動(dòng)脈左前降支45min后再灌注120min。熒光定量PCR檢測(cè)miR-208a的表達(dá)變化；Evans藍(lán)染色和氯化三苯基四氮唑(triphenyl tetrazolium chloride, TTC)染色來(lái)檢測(cè)心肌梗死情況;HE染色檢測(cè)心肌組織形態(tài)結(jié)構(gòu)變化；末端脫氧核苷酸轉(zhuǎn)移酶介導(dǎo)的末端標(biāo)記技術(shù)(TUNEL)檢測(cè)各組心肌細(xì)胞凋亡情況；Western blot檢測(cè)心肌細(xì)胞凋亡標(biāo)志物Caspase-3的變化。3,采用antagomir調(diào)控miRNA的表達(dá),檢測(cè)是否能夠減緩缺血再灌注損傷：構(gòu)建大鼠缺血再灌注模型,將大鼠隨機(jī)分為缺血再灌注組(I/R)、control antagomir注射后再行缺血再灌注組(I/R+anta-control), miR-208a antagomir注射后再行缺血再灌注組(I/R+anta-miR-208a). I/R組開(kāi)胸結(jié)扎前降支45min后再灌注120min。I/R+anta-control或I/R+anta-miR-208a為缺血再灌注前2天注射2nmol劑量的相應(yīng)antagomir。熒光定量PCR檢測(cè)miR-208a的表達(dá)變化；Evans藍(lán)染色和TCC檢測(cè)心肌梗死情況；HE染色檢測(cè)心肌組織形態(tài)結(jié)果變化；TUNEL法檢測(cè)各組心肌細(xì)胞凋亡情況；Western blot檢測(cè)心肌細(xì)胞凋亡標(biāo)志物Caspase-3的變化。熒光定量PCR檢測(cè)心房利鈉因子(atrial natriuretic factor,ANF)和腦鈉肽(brain natriuretic peptide, BNP)的表達(dá)水平,同時(shí)采用LDH檢測(cè)試劑盒檢測(cè)各組大鼠血清LDH水平以評(píng)估心肌功能。4,通過(guò)生物信息學(xué)的方法預(yù)測(cè)miR-208a的潛在靶向mRNA,通過(guò)熒光素酶報(bào)告實(shí)驗(yàn)初步篩選miR-208a的靶基因,并運(yùn)用流式細(xì)胞術(shù)檢測(cè)轉(zhuǎn)染后各組細(xì)胞的凋亡情況。結(jié)果：1, miR-1/208a/499的表達(dá)在體外循環(huán)前和再灌注后出現(xiàn)了明顯的變化(P 0.05), miR-21在本研究中未觀測(cè)到變化(P0.05)。miR-1/208a的表達(dá)水平在主動(dòng)脈阻斷45min時(shí)出現(xiàn)顯著變化(P0.05),但當(dāng)再灌注60min后顯著增加(P0.05),并持續(xù)至術(shù)后24h(P0.05)。miR-1/208a的表達(dá)變化模式同傳統(tǒng)生理指標(biāo)CK-MB和cTnl的水平變化相似,而且miR-208a的變化較miR-1迅速。與之相反,miR-499的表達(dá)水平在再灌注后持續(xù)降低一直到術(shù)后24h(P0.05)。而且它的變化同CK-MB和cTnl的水平變化呈負(fù)相關(guān)。2,通過(guò)心電圖和染色檢測(cè)結(jié)果表明,大鼠的心臟缺血再灌注損傷模型成功構(gòu)建。與Sham組相比較,I/R組的大鼠心肌缺血區(qū)miR-208a顯著升高(P0.05)；細(xì)胞凋亡率明顯增加(P0.05),凋亡標(biāo)志物Caspase-3表達(dá)水平升高(P0.05),剪切體被激活。這暗示了miR-208a可能與心肌細(xì)胞的凋亡存在一定的關(guān)聯(lián)性。3,大鼠轉(zhuǎn)染antagomir后進(jìn)行缺血再灌注損傷造模,隨后進(jìn)行各項(xiàng)指標(biāo)的檢測(cè)。結(jié)果發(fā)現(xiàn),I/R+anta-miR-208a組中的miR-208a的表達(dá)水平明顯低于其余兩組(I/R和I/R+anta-control) (P0.05),表達(dá)明顯受到抑制。TCC檢測(cè)結(jié)果發(fā)現(xiàn)I/R+anta-miR-208a組的心肌梗死范圍明顯少于其余兩組(P0.05)；TUNEL檢測(cè)結(jié)果顯示I/R+anta-miR-208a組的心肌細(xì)胞凋亡率顯著降低,Caspase-3表達(dá)水平也同樣顯著降低(P0.05); ANF和BNP以及血清中LDH的水平在anta-miR-208a處理后均顯著降低(P0.05),說(shuō)明心肌功能障礙有所減輕。各個(gè)指標(biāo)在I/R和I/R+anta-control兩組中均無(wú)顯著性差異(P0.05)。4,根據(jù)生物信息學(xué)分析,我們預(yù)測(cè)miR-208a與GATA4和QKI5的3'UTR區(qū)域有直接的結(jié)合位點(diǎn)。進(jìn)一步對(duì)之前的樣本進(jìn)行GATA4和QKI5表達(dá)水平檢測(cè)發(fā)現(xiàn),I/R組的GATA4和QKI5表達(dá)水平較Sham組顯著降低；與I/R組相比,抑制miR-208a預(yù)處理能夠升高GATA4和QKI5的表達(dá),二者存在負(fù)相關(guān)性。雙熒光素酶報(bào)告基因檢測(cè)證實(shí)了miR-208a同GATA4而非QKI5的靶向關(guān)系。結(jié)論：1,在體外循環(huán)的開(kāi)胸手術(shù)過(guò)程中,miR-1/208a/499出現(xiàn)了顯著變化,其中miR-208a反應(yīng)更加迅速。2,在大鼠缺血再灌組損傷模型中,降低miR-208a的表達(dá)水平能夠明顯抑制心肌細(xì)胞的凋亡,減緩由于缺血再灌注所導(dǎo)致的心肌功能障礙,具有心臟保護(hù)作用。3, miR-208a的這種作用可能通過(guò)靶向GATA4或影響QK15相關(guān)信號(hào)通路來(lái)實(shí)現(xiàn)。
[Abstract]:At present, thoracotomy has been widely used in the treatment of various types of heart diseases. Cardiopulmonary bypass is a vital means in open heart surgery. However, some studies have revealed that the operation itself can cause damage to various organs in the body, most of which are accompanied by ischemia-reperfusion injury in tissues and organs. Studying the mechanism of ischemia-reperfusion injury, trying to avoid or weaken this clinical problem will benefit the patient.MiRNAs is short fragment single strand non coding RNAs, which can target mRNAs after transcriptional regulation. Continuous accumulation of research shows that miRNAs plays an important role in the development of ischemia-reperfusion injury, and it may become a treatment. Objective: To explore the potential targets of myocardial ischemia reperfusion injury. Objective: To investigate the changes of miRNAs related to myocardium during cardiopulmonary bypass in cardiopulmonary bypass, and to study the key miRNA of miR-208a, and to detect the role of miR-208a in ischemia reperfusion injury by rat ischemia-reperfusion model. The early diagnosis of blood reperfusion provides a theoretical basis for prevention and treatment, and provides potential targets for future molecular therapy. Methods: 1, qRT-PCR was used to detect the level of expression of miR-1/21/208a/499 at four time points during open thoracic surgery for cardiopulmonary bypass in 15 patients with rheumatic heart disease (pre operation, 45 mmin of main artery occlusion, reperfusion after 60mmin, postoperative 24h); The levels of the traditional physiological and biochemical indexes of creatine kinase isoenzyme (CK-MB) and troponin 1 (cTnI) were detected. By statistical analysis, the correlation.2 between them was detected and the rat model of ischemia reperfusion was constructed. The rats were randomly divided into the sham operation group (Sham) and the ischemia reperfusion group (I/R). The rats in the Sham group were only open to the chest, and the I/R group opened the chest to ligation coronal. The expression of miR-208a was detected by 120min. fluorescence quantitative PCR reperfusion after the left anterior descending branch of the artery 45min; Evans blue staining and three phenyl tetrazolium chloride (triphenyl tetrazolium chloride, TTC) staining were used to detect myocardial infarction; HE staining was used to detect the changes in the morphological structure of the myocardium; terminal deoxynucleotidyl transferase mediated terminal labeling The technique (TUNEL) was used to detect the apoptosis of cardiac myocytes in each group; Western blot was used to detect the changes of myocardial apoptosis marker Caspase-3,.3, and antagomir to regulate the expression of miRNA, and to detect whether the ischemia reperfusion injury could be slowed down: the rat model of ischemia reperfusion was constructed and the rats were randomly divided into ischemic reperfusion group (I/R), control antagomir Ischemia-reperfusion group (I/R+anta-control) was performed after injection, and ischemia reperfusion group (I/R+anta-miR-208a) was performed after miR-208a antagomir injection. I/R group was injected with 120min.I/R+anta-control or I/R+anta-miR-208a before ligation of thoracic ligation, and 120min.I/R+anta-control or I/R+anta-miR-208a was injected at 2 days before ischemia-reperfusion, and the corresponding antagomir. fluorescence quantitative PCR detection of miR-2 was detected. 08A expression changes; Evans blue staining and TCC detection of myocardial infarction; HE staining to detect changes in myocardial tissue morphology; TUNEL method to detect the apoptosis of cardiac myocytes in each group; Western blot to detect the change of Caspase-3 in cardiac myocyte apoptosis marker. Fluorescence quantitative PCR detection of atrial natriuretic factor (atrial natriuretic factor,) and The expression level of brain natriuretic peptide (BNP) and LDH detection kit were used to detect the serum LDH level in each group to evaluate the myocardial function.4. The potential target mRNA of miR-208a was predicted by bioinformatics. The target gene of miR-208a was screened by the luciferase reporter experiment and the flow cytometry was used to detect the target gene. Results: 1, 1, the expression of miR-1/208a/499 appeared obvious changes before and after cardiopulmonary bypass (P 0.05). The expression level of miR-21 in this study was not observed in this study (P0.05), and the expression level of.MiR-1/208a was significantly changed when the aorta blocked 45min (P0.05), but increased significantly after reperfusion of 60min. In addition (P0.05), the expression pattern of 24h (P0.05).MiR-1/208a was similar to that of the traditional physiological indexes of CK-MB and cTnl, and the change of miR-208a was faster than that of miR-1. The results of electrocardiogram and staining showed that the model of myocardial ischemia reperfusion injury was successfully constructed in rats. Compared with group Sham, the myocardial ischemia area of rats in group I/R increased significantly (P0.05), the apoptosis rate increased significantly (P0.05), the level of Caspase-3 expression of apoptosis marker increased (P0.05), and the shear body was activated in I/R. This suggests that miR-208a may have a certain correlation with the apoptosis of cardiac myocytes, the rat model of ischemia reperfusion injury after transfection of antagomir, and then the detection of various indexes. The results showed that the expression level of miR-208a in the I/R+anta-miR-208a group was significantly lower than that of the remaining two groups (I/R and I/R+anta-control) (P0.05), and the expression of miR-208a in the I/R+anta-miR-208a group was clearly expressed. The results of.TCC detection showed that the infarct range in group I/R+anta-miR-208a was significantly less than that of the other two groups (P0.05); TUNEL detection showed that the apoptosis rate of myocardial cells in I/R+anta-miR-208a group decreased significantly, and the level of Caspase-3 expression decreased significantly (P0.05), ANF and BNP and the level of LDH in serum were in anta-miR-208a. There was a significant decrease (P0.05), indicating a reduction in myocardial dysfunction. Each index had no significant difference in I/R and I/R+anta-control two groups (P0.05).4. According to bioinformatics analysis, we predicted a direct binding site between miR-208a and the 3'UTR region of GATA4 and QKI5. Further GATA4 and QKI5 expressed water for the previous samples. The level of GATA4 and QKI5 expression in the I/R group was significantly lower than that in the Sham group. Compared with the I/R group, the inhibition of miR-208a preconditioning could increase the expression of GATA4 and QKI5, and there was a negative correlation between the two. The double luciferase reporter gene test confirmed the target relationship between miR-208a and GATA4 but not QKI5. Conclusion: 1, open thoracotomy in cardiopulmonary bypass. During the process, there are significant changes in miR-1/208a/499, in which the miR-208a reaction is more rapid.2. In the rat model of ischemia reperfusion injury, the decrease of the expression level of miR-208a can obviously inhibit the apoptosis of cardiac myocytes and slow down the myocardial dysfunction due to ischemia reperfusion, which has the effect of cardiac protection,.3, miR-208a. It may be achieved by targeting GATA4 or affecting QK15 related signaling pathways.
【學(xué)位授予單位】：昆明醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R542.2

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