本文選題：缺血再灌注損傷 + 血管再生　； 參考：《青島大學(xué)》2017年博士論文

【摘要】：目的:近年研究發(fā)現(xiàn),SHH信號通路參與了多種動物缺血模型中的血管再生,包括腦缺血,骨骼肌缺血、角膜及肢體缺血等。然而,SHH信號通路在心肌缺血再灌注中的研究卻很少,并且給予重組人SHH蛋白干預(yù)是否對心臟微血管內(nèi)皮細(xì)胞具有保護(hù)作用及其潛在作用機(jī)制是否與激活SHH-Patched-SMO-Gli信號通路有關(guān)尚無文獻(xiàn)報道。而且SHH在急性心肌梗死后冠狀動脈側(cè)枝循環(huán)的形成中發(fā)揮何種作用及其機(jī)制尚無相關(guān)研究。因此,我們將從以下方面探討:1.研究重組人SHH蛋白對CMECs細(xì)胞凋亡與增殖的影響,探討SHH信號通路激活對大鼠CMECs缺血再灌注損傷后促血管再生的作用及其潛在機(jī)制,為臨床上心肌缺血再灌注損傷的防治提供理論依據(jù)。2.探討急性心肌梗死患者冠狀動脈側(cè)枝循環(huán)建立與血漿SHH水平的相關(guān)性,了解SHH在急性心肌梗死后冠狀動脈側(cè)枝循環(huán)形成中的作用,為臨床上急性心肌梗死治療提供新的治療手段。方法:原代培養(yǎng)SD雄性大鼠心臟微血管內(nèi)皮細(xì)胞(Cardiac microvascular endothelial cells,CMECs),建立氧糖剝奪/復(fù)氧(Oxygen-glucose deprivation/reoxygenation,OGD/R)模擬體外缺血再灌注損傷模型,給予外源性重組人SHH蛋白、Cyclopamine處理,RT-PCR檢測對照組和OGD組中SHH的mRNA水平;用MTT和Annexin-V-FITC/PI雙標(biāo)記流式細(xì)胞術(shù)分別檢測細(xì)胞活力和細(xì)胞凋亡;應(yīng)用ELISA和RT-PCR方法分別檢測血管新生因子(VEGF,FGF,Ang-1)的血清水平和mRNA表達(dá)水平;應(yīng)用RT-PCR和Western blotting方法分別檢測Sonic hedgehog(SHH)信號通路靶分子(SHH,SMO,Patched-1,Gli-1,Gli-2)的mRNA和蛋白表達(dá)水平。在臨床試驗中,選擇2014年12月-2016年6月于濟(jì)寧市第一人民醫(yī)院心血管診療中心收治的行急診PCI術(shù)的急性心肌梗死患者298例為研究對象,懫用盲法進(jìn)行Rentrop評分,分為無側(cè)枝循環(huán)組,側(cè)支循環(huán)較差組和側(cè)性循環(huán)較好組3組。并且采集患者年齡、性別等基本臨床資料以及實驗室檢查的結(jié)果,確定心肌梗死相關(guān)動脈,并記錄梗死發(fā)病的時間。留取患者的術(shù)前血漿標(biāo)本,并采用ELISA法測定血漿SHH水平。懫用SPSS20.0軟件進(jìn)行統(tǒng)計學(xué)分析,從而探討急性心肌梗死患者冠狀動脈側(cè)枝循環(huán)建立與血漿SHH水平的相關(guān)性。結(jié)果:1.與正常對照組相比,OGD組SHH的mRNA表達(dá)水平明顯升高,差異有統(tǒng)計學(xué)意義(p0.05),上述結(jié)果表明氧糖剝奪/復(fù)氧cmecs缺血再灌注損傷可以激活shh信號通路,促使shhmrna表達(dá)水平升高。2.與正常對照組相比,加入外源性重組人shh蛋白后,正常氧糖條件下cmecs的細(xì)胞活力顯著增加,但其影響可以被抑制劑cyclopamine顯著消減(p0.05),上述結(jié)果表明shh可以促進(jìn)正常氧糖條件下cmecs的細(xì)胞活力增強(qiáng)。相反,當(dāng)細(xì)胞在ogd/r條件下,細(xì)胞活力與正常對照組相比顯著減弱(p0.05),表明氧糖剝奪/復(fù)氧會導(dǎo)致細(xì)胞活力受到抑制;而在shh處理后與ogd組相比細(xì)胞活力顯著增加(p0.05);但其影響也可以被抑制劑cyclopamine顯著消減(p0.05),上述結(jié)果表明shh可以促進(jìn)氧糖剝奪/復(fù)氧cmecs的細(xì)胞活力增強(qiáng)。3.與正常對照組相比,加入外源性重組人shh蛋白后,正常氧糖條件下cmecs的細(xì)胞凋亡僅稍減少(4.09%),差異無統(tǒng)計學(xué)意義(p0.05);當(dāng)給予抑制劑cyclopamine處理后cmecs的細(xì)胞凋亡較正常對照組相比僅稍增加(6.43%),差異無統(tǒng)計學(xué)意義(p0.05)。在ogd/r條件下,cmecs細(xì)胞凋亡較正常對照組增加(12.4%),差異有統(tǒng)計學(xué)意義(p0.05),表明ogd/r導(dǎo)致了cmecs的細(xì)胞凋亡顯著增加;當(dāng)我們給予激活劑shh蛋白處理后cmecs的細(xì)胞凋亡出現(xiàn)顯著減少(5.23%),差異有統(tǒng)計學(xué)意義(p0.05);給予抑制劑cyclopamine處理后發(fā)現(xiàn)cmecs細(xì)胞凋亡與ogd組相比顯著增加(16.7%),差異有統(tǒng)計學(xué)意義(p0.01),上述結(jié)果表明shh可以抑制氧糖剝奪/復(fù)氧cmecs的細(xì)胞凋亡。4.與正常對照組相比,加入外源性重組人shh蛋白后,正常氧糖條件下血管新生因子vegf,fgf和ang-1的血清水平和mrna表達(dá)顯著增加,差異有統(tǒng)計學(xué)意義(p0.05),但是shh的生物學(xué)效應(yīng)可以被shh信號通路特異性抑制劑cyclopamine所抑制(p0.01),上述結(jié)果表明shh可以促進(jìn)正常氧糖條件下cmecs的血管新生。在ogd/r條件下,血管新生因子vegf,fgf和ang-1的血清水平和mrna表達(dá)顯著增加,差異有統(tǒng)計學(xué)意義(p0.01),同樣shh的生物學(xué)效應(yīng)可以被shh信號通路特異性抑制劑cyclopamine所抑制(p0.01),上述結(jié)果表明shh可以促進(jìn)氧糖剝奪/復(fù)氧cmecs的血管新生。5.加入外源性重組人shh蛋白后,在ogd/r條件下,shh信號通路中靶分子shh,smo,patched-1,gli-1和gli-2的mrna表達(dá)水平明顯升高,與ogd組相比,差異有統(tǒng)計學(xué)意義(p0.05),但是shh的生物學(xué)效應(yīng)可以被shh信號通路特異性抑制劑cyclopamine所抑制(p0.01)。同樣,在ogd/r條件下,shh信號通路中靶分子shh,smo,patched-1,gli-1和gli-2的蛋白表達(dá)水平明顯升高,與ogd組相比,差異有統(tǒng)計學(xué)意義(p0.05),但shh的生物學(xué)效應(yīng)也可以被shh信號通路特異性抑制劑Cyclopamine所抑制(p0.01)。以上結(jié)果表明重組人SHH蛋白在激活SHH信號通路的下游信號蛋白表達(dá)過程中扮演重要的角色。6.急性心肌梗死患者冠脈側(cè)枝循環(huán)較差組血漿SHH水平與對照組相比差異無統(tǒng)計學(xué)意義(p0.05);并且冠脈側(cè)枝循環(huán)較好組中血漿SHH水平顯著高于冠脈側(cè)枝循環(huán)較差組以及對照組(p0.01),提示在急性心肌梗死患者冠脈側(cè)枝循環(huán)評分較高的患者中其血漿SHH含量也比較高(p0.01),并且其相關(guān)性獨(dú)立于年齡、性別、BMI、高血壓、糖尿病家族史、心肌梗死類型、吸煙史、飲酒史、空腹血糖水平、血肌酐、血尿素氮、總膽固醇、甘油三酯、HDL-C、BNP等危險因素單獨(dú)存在。結(jié)論:1.SHH對缺血再灌注損傷的心臟微血管內(nèi)皮細(xì)胞具有保護(hù)作用;CMECs缺血再灌注損傷存在著SHH信號通路的激活;外源性加入重組人SHH蛋白可以增強(qiáng)細(xì)胞活力,減輕細(xì)胞凋亡,上調(diào)血管新生因子VEGF,FGF和Ang-1的表達(dá),促進(jìn)新生血管形成,提示SHH信號通路激活在CMECs缺血再灌注損傷后血管再生過程中發(fā)揮著舉足輕重的作用,可能成為心肌缺血再灌注損傷的潛在治療靶點(diǎn)。2.急性心肌梗死患者冠狀動脈側(cè)支循環(huán)建立與血漿SHH水平明顯相關(guān),且血漿SHH水平獨(dú)立于年齡、性別、BMI、高血壓、糖尿病家族史、心肌梗死類型、吸煙史、飲酒史、空腹血糖水平、血肌酐、血尿素氮、總膽固醇、甘油三酯、HDL-C、BNP等危險因素作用于急性心肌梗死患者缺血心肌區(qū)域側(cè)枝循環(huán)的形成過程。提示可以將SHH血清水平作為急性心肌梗死患者冠狀動脈側(cè)枝循環(huán)形成狀況好壞的預(yù)測因子。
[Abstract]:Objective: in recent years, SHH signaling pathway has been found to be involved in vascular regeneration in a variety of animal ischemic models, including cerebral ischemia, skeletal muscle ischemia, corneal and limb ischemia. However, there are few studies on the SHH signaling pathway in myocardial ischemia reperfusion, and the intervention of recombinant human SHH protein to the cardiac microvascular endothelial cells is guaranteed. There is no literature about whether the protective effect and its potential mechanism are related to the activation of the SHH-Patched-SMO-Gli signaling pathway. And what role and mechanism of SHH in the formation of coronary collateral circulation after acute myocardial infarction has not yet been studied. Therefore, we will discuss the following aspects: 1. the study of recombinant human SHH protein to CMECs The effect of apoptosis and proliferation, the effect of SHH signaling pathway activation on vascular regeneration after CMECs ischemia-reperfusion injury in rats and its potential mechanism, provide a theoretical basis for the prevention and treatment of myocardial ischemia reperfusion injury in clinical,.2. study on the correlation between the establishment of coronary artery lateral branch circulation and plasma SHH level in patients with acute myocardial infarction, The role of SHH in the formation of coronary collateral circulation after acute myocardial infarction provides a new treatment for the treatment of acute myocardial infarction. Methods: the primary culture of SD male rat cardiac microvascular endothelial cells (Cardiac microvascular endothelial cells, CMECs), and the establishment of oxygen glucose deprivation / reoxygenation (Oxygen-glucose deprivation/reox). Ygenation, OGD/R) simulated in vitro ischemia-reperfusion injury model, gave exogenous recombinant human SHH protein, Cyclopamine treatment, RT-PCR detected the mRNA level of SHH in the control group and OGD group. MTT and Annexin-V-FITC/PI double standard flow cytometry were used to detect cell viability and apoptosis respectively; ELISA and RT-PCR methods were used to detect angiogenesis respectively. The serum level of factor (VEGF, FGF, Ang-1) and the level of mRNA expression; the RT-PCR and Western blotting methods were used to detect the protein expression level of Sonic hedgehog (SHH) signaling pathway target molecule (SHH, SMO, Ang-1). In the clinical trial, the cardiovascular diagnosis of the first people's Hospital of Jining was selected in June. 298 patients with acute myocardial infarction treated with emergency PCI were treated with blind method of Rentrop. They were divided into no collateral circulation group, poor collateral circulation group and 3 group with better lateral circulation. The basic clinical data of age, sex and laboratory examination were collected, and the correlation of myocardial infarction was determined. Blood plasma samples were recorded and plasma SHH levels were measured by ELISA method. The correlation between coronary artery collateral circulation establishment and plasma SHH level was investigated by SPSS20.0 software. Results: 1. compared with the normal control group, the mRNA of SHH in the OGD group was mRNA. The expression level was significantly increased (P0.05). The results showed that oxygen glucose deprivation / reoxygenation CMECs ischemia-reperfusion injury could activate the Shh signaling pathway, promote the increase of shhmrna expression level and.2. compared with the normal control group. After adding exogenous recombinant human Shh protein, the cell viability of CMECs increased significantly under normal oxygen glucose condition. But the effect could be significantly reduced by the inhibitor cyclopamine (P0.05). The results showed that Shh could promote the cell viability of CMECs under the condition of normal oxygen glucose. On the contrary, the cell viability was significantly decreased compared with the normal control group (P0.05) under ogd/r conditions (P0.05), indicating that the oxygen glucose deprivation / reoxygenation could lead to the inhibition of cell viability; and in SH, the cell viability was inhibited. After h treatment, the cell viability was significantly increased (P0.05) compared with the OGD group, but the effect could also be significantly reduced by the inhibitor cyclopamine (P0.05). The results indicated that Shh could promote the cell viability of the oxygen glucose deprivation / reoxygenation CMECs as compared with the normal control group. After adding the exogenous recombinant human Shh protein, the CMECs cells in the normal oxygen glucose CMECs were the cells. There was only a slight decrease in apoptosis (4.09%), the difference was not statistically significant (P0.05). When the inhibitor cyclopamine was treated, the apoptosis of CMECs was only slightly increased (6.43%) compared with that of the normal control group (P0.05). In ogd/r, the apoptosis of CMECs cells was increased (12.4%), and the difference was statistically significant (P0.05), indicating og D/r resulted in a significant increase in apoptosis in CMECs; the apoptosis of CMECs cells decreased significantly (5.23%) when we treated the activator Shh protein (P0.05), and the apoptosis of CMECs cells was significantly increased (16.7%) compared with that of OGD group (P0.01), and the difference was statistically significant (P0.01). The results showed that Shh could inhibit the apoptosis of oxygen glucose deprivation / reoxygenation CMECs cell apoptosis.4. compared with the normal control group. After adding exogenous recombinant human Shh protein, the serum level of angiogenic factor VEGF, FGF and Ang-1 increased significantly under normal oxygen glucose conditions, and the difference was statistically significant (P0.05), but the biological effect of Shh could be carried out by SHH letter. The signal pathway specific inhibitor cyclopamine inhibited (P0.01). The results showed that Shh could promote the angiogenesis of CMECs under the condition of normal oxygen glucose. The serum level and mRNA expression of the angiogenesis factor VEGF, FGF and Ang-1 increased significantly under ogd/r conditions, and the difference was statistically significant (P0.01), and the biological effect of the same Shh could be expressed in Shh letter. The signal transduction pathway specific inhibitor cyclopamine inhibits (P0.01). The results show that Shh can promote the addition of recombinant human Shh protein to the angiogenic.5. of oxygen glucose deprivation / reoxygenation CMECs. In ogd/r, the target molecules Shh, SMO, patched-1, Gli-1, and the expression level of the Shh signaling pathway are significantly higher than those of the shh. There were statistical significance (P0.05), but the biological effects of Shh could be inhibited by the Shh signaling pathway specific inhibitor cyclopamine (P0.01). Similarly, the protein expression levels of the target molecules Shh, SMO, patched-1, Gli-1 and gli-2 were significantly higher in the Shh signaling pathway under the ogd/r condition, and the difference was statistically significant compared with those of the group. Biological effects can also be inhibited by the Shh signaling pathway specific inhibitor Cyclopamine (P0.01). The results show that the recombinant human SHH protein plays an important role in the process of activating the downstream signal protein in the SHH signaling pathway. The plasma SHH level of the coronary collateral circulation group in patients with acute myocardial infarction is different from that of the control group. There was no statistical significance (P0.05), and the plasma SHH level in the better coronary collateral circulation group was significantly higher than that of the poor coronary collateral circulation group and the control group (P0.01), suggesting that the plasma SHH content was higher in patients with higher coronary collateral circulation score (P0.01) in patients with acute myocardial infarction (P0.01), and the correlation was independent of age, sex, BMI, Hypertension, diabetes family history, myocardial infarction type, smoking history, drinking history, fasting blood glucose level, blood creatinine, blood urea nitrogen, total cholesterol, triglyceride, HDL-C, BNP and other risk factors exist alone. Conclusion: 1.SHH has protective effect on cardiac microvascular intravascular cells of ischemia-reperfusion injury; CMECs ischemia reperfusion injury has SHH letter. The extraneous addition of recombinant human SHH protein can enhance cell vitality, reduce cell apoptosis, increase the expression of angiogenic factor VEGF, FGF and Ang-1, and promote the formation of neovascularization, suggesting that the activation of SHH signaling pathway plays an important role in the process of vascular regeneration after CMECs ischemia reperfusion injury, and may become the heart. The potential therapeutic target of myocardial ischemia reperfusion injury in.2. patients with acute myocardial infarction is closely related to the level of plasma SHH, and the level of plasma SHH is independent of age, sex, BMI, hypertension, family history of diabetes, myocardial infarction type, smoking history, drinking wine history, fasting blood glucose level, serum creatinine, blood urea nitrogen, total gallbladder. Risk factors such as alcohols, triglycerides, HDL-C, BNP and other risk factors are used in the formation of collateral circulation in the ischemic myocardium of patients with acute myocardial infarction. It is suggested that the serum level of SHH can be used as a predictor of the condition of the formation of coronary collateral circulation in patients with acute myocardial infarction.

【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R54

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9 程華;孫芳玲;艾厚喜;張麗;蔣瑩;王文;;Wnt信號通路與血管發(fā)生[A];全國第三次麻醉藥理學(xué)術(shù)會議論文集[C];2012年

10 李林;;利用小分子探針研究經(jīng)典Wnt信號通路的信號轉(zhuǎn)導(dǎo)機(jī)制[A];中國生物化學(xué)與分子生物學(xué)會第十一次會員代表大會暨2014年全國學(xué)術(shù)會議論文集——專題報告七[C];2014年

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