本文關(guān)鍵詞： 腦血管內(nèi)皮細(xì)胞 乏氧 腺苷酸活化蛋白激酶 雷帕霉素靶蛋白 自噬　出處：《鄭州大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：背景與目的大腦的是高血流量、高耗氧量的器官,腦的重量?jī)H占體重的2%,血流量卻占心輸出量的15%左右,耗氧量約占全身耗氧量的20%。但同時(shí),大腦的能源儲(chǔ)備極少,幾乎只能利用腦循環(huán)提供的氧和葡萄糖進(jìn)行有氧代謝,對(duì)腦循環(huán)有高度的依賴性。一旦發(fā)生完全性缺血缺氧超過5分鐘,腦細(xì)胞就會(huì)發(fā)生不可逆性死亡,所以腦循環(huán)功能的正常意義重大,尤其是在急性腦梗死等缺血缺氧條件下,腦循環(huán)功能決定了腦部病變的發(fā)展和轉(zhuǎn)歸。腦循環(huán)是一個(gè)高度專業(yè)化的血管床,腦血管內(nèi)皮細(xì)胞在腦循環(huán)的調(diào)節(jié)中起著重要的作用。腦血管內(nèi)皮細(xì)胞在一些病理情況下如缺血缺氧時(shí),經(jīng)常會(huì)受到損傷,我們以往對(duì)腦缺血缺氧的研究都主要集中在神經(jīng)元、神經(jīng)膠質(zhì)細(xì)胞、神經(jīng)干細(xì)胞等方面,對(duì)腦血管內(nèi)皮細(xì)胞的研究不多。除了常見的腦血管病以外,許多腦部疾病均伴發(fā)有缺血缺氧,所以研究腦血管內(nèi)皮細(xì)胞缺血缺氧時(shí)的功能改變及其機(jī)制有重要的臨床意義。缺氧時(shí),腦血管內(nèi)皮細(xì)胞的功能改變主要為：以增殖、凋亡、自噬等為表現(xiàn)的細(xì)胞生存改變和內(nèi)分泌變化,而生存改變是基礎(chǔ),所以本實(shí)驗(yàn)主要研究缺氧時(shí)血管內(nèi)皮細(xì)胞的增殖、凋亡和自噬的變化,并探討其機(jī)制。腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)是代謝的感應(yīng)器,哺乳動(dòng)物AMPK是由三個(gè)亞基組成的異三聚體復(fù)合體,包括α亞基、p調(diào)控亞基和γ亞基。a催化亞基含有一個(gè)高度保守的絲氨酸蘇氨酸激酶結(jié)構(gòu)域,靠近活化環(huán)的N-末端,Thr-172磷酸化對(duì)酶的活性起關(guān)鍵作用；p亞基沒有催化活性,可能與細(xì)胞內(nèi)AMPKαβγ復(fù)雜體裝配和細(xì)胞傳感糖原相關(guān)；γ亞基通過感知細(xì)胞內(nèi)ATP、ADP和AMP的濃度調(diào)節(jié)酶的活性。通過激活A(yù)MPK保持能量的平衡代謝途徑(ATP生產(chǎn))和抑制合成代謝途徑(ATP消耗)。AMPK在營(yíng)養(yǎng)條件差條件下激活,而營(yíng)養(yǎng)豐富的條件下失去活性。AMPK激活下游的效應(yīng)包括脂質(zhì)和糖代謝、能量消耗、免疫反應(yīng)、細(xì)胞生長(zhǎng)和極性。AMPK廣泛存在于人體多種組織,但在腦血管內(nèi)皮細(xì)胞的研究不多。哺乳動(dòng)物雷帕霉素靶蛋白(Mammalian target of rapamycin, mTOR)是調(diào)節(jié)細(xì)胞生長(zhǎng)的一種絲氨酸蘇氨酸激酶。在AMPK激活后mTOR活性抑制。mTOR活化都需要來自營(yíng)養(yǎng)成分(葡萄糖,氨基酸)和生長(zhǎng)因子的積極信號(hào)。在哺乳動(dòng)物中,mTORC1復(fù)合物(mTOR complex 1, mTORC1)是由四個(gè)已知亞基構(gòu)成：Raptor、PRAS40、mLST8和mTOR。mTORC1對(duì)營(yíng)養(yǎng)信號(hào)敏感,可被細(xì)菌的大環(huán)內(nèi)酯類雷帕霉素很快抑制,控制細(xì)胞的生長(zhǎng)、血管生成及代謝。相反,mTORC2對(duì)營(yíng)養(yǎng)信號(hào)是不敏感的,也不能被雷帕霉素很快抑制。mTORC1的兩個(gè)已知底物是4EBP1和p70核糖體S6激酶。除了這些生長(zhǎng)刺激信號(hào)激活]mTORC1,復(fù)合體可通過各種細(xì)胞應(yīng)激迅速失活,從而保證細(xì)胞不受損害。mTORC1復(fù)合體的一個(gè)獨(dú)特的方面是,它是依賴于養(yǎng)分利用而表現(xiàn)激酶活性。在低氧氣條件下,細(xì)胞激活一系列關(guān)鍵通路而適應(yīng)生存,其中大多數(shù)途徑的是由轉(zhuǎn)錄因子缺氧誘導(dǎo)因子1(Hypoxia inducible factor 1,HIF-1)調(diào)節(jié)的,這在很大程度上依賴于細(xì)胞利用氧的能力作為信號(hào)來控制]HIF-1α的穩(wěn)定性和轉(zhuǎn)錄活性�；罨腍IF-1是由HIF-1α和HIF-1β兩亞基組成構(gòu)成異源二聚體,HIF-1α受氧濃度的精密調(diào)節(jié)且不穩(wěn)定,亞基與氧水平無關(guān)。HIF-1β是乏氧誘導(dǎo)反應(yīng)HIF-1α的關(guān)鍵分子,乏氧條件下,它被誘導(dǎo)表達(dá)。以前的研究證明在神經(jīng)系統(tǒng)發(fā)揮重要作用,但在腦血管內(nèi)皮細(xì)胞的作AMPK用還知之甚少,本課題我們將用分離的小鼠腦血管內(nèi)皮細(xì)胞研究乏氧條件下在腦血管內(nèi)皮細(xì)胞的功能,包括腦血管內(nèi)皮細(xì)胞的增殖和凋亡,并研究其AMPK功能是否通過HIF-1進(jìn)行的。自噬是細(xì)胞維持其細(xì)胞穩(wěn)態(tài)的一個(gè)重要機(jī)制,我們將研究在腦血管內(nèi)皮細(xì)胞自噬中的作用及機(jī)制。AMPK-mTOR第一部分乏氧條件-下在腦血管內(nèi)皮細(xì)胞增殖及介導(dǎo)線粒體途AMPK徑凋亡中的作用目的：研究腦血管內(nèi)細(xì)胞在乏氧條件下表達(dá)的情況。明確HIF-1是否AMPK參與了乏氧條件下的活化。研究乏氧條件下AMPK對(duì)血管內(nèi)皮細(xì)胞增殖、AMPK凋亡的作用及機(jī)制。方法：首先分離出小鼠腦血管內(nèi)皮細(xì)胞(Cerebrovascular endothelial cells, CVEC),然后將其在乏氧(1%02)和常氧條件下進(jìn)行培養(yǎng),分別觀察乏氧0、4、12和24小時(shí)的MPK表達(dá),用Real time PCR法檢測(cè)AMPK的表達(dá)。為明確HIF-1是否參與了乏氧條件下AMPK的活化,我們將小鼠血管內(nèi)皮細(xì)胞在乏氧條件下培養(yǎng),并用HIF-1α抑制劑處理細(xì)胞,檢測(cè)細(xì)胞的AMPK活性。研究AMPK在腦血管內(nèi)皮細(xì)胞中的增殖和凋亡的作用,用MTT法檢測(cè)血管內(nèi)皮細(xì)胞在乏氧條件下的增殖,并用AMPK shRNA及AMPK抑制劑下調(diào)AMPK后觀察血管內(nèi)皮細(xì)胞的增殖。用流式細(xì)胞儀檢測(cè)乏氧條件下血管內(nèi)皮細(xì)胞的凋亡率,并用AMPK shRNA下調(diào)AMPK后觀察血管內(nèi)皮細(xì)胞的凋亡率。同時(shí)用Western blot法檢測(cè)腦血管內(nèi)皮細(xì)胞中Bcl-2、Cl-caspase3的表達(dá),用活性氧檢測(cè)試劑盒檢測(cè)乏氧下下調(diào)AMPK后腦血管內(nèi)皮細(xì)胞ROS的產(chǎn)生量。結(jié)果：我們發(fā)現(xiàn)在小鼠腦血管內(nèi)皮細(xì)胞主要表達(dá)AMPKα2,且磷酸化AMPK在乏氧條件下增加。當(dāng)抑HIF-1α后,磷酸化的AMPK下降,同時(shí)AMPK也下降,證明乏氧能促進(jìn)HIF-1α表達(dá),能促進(jìn)AMPK的活化。AMPK能促進(jìn)細(xì)胞增殖。AMPK能抑制細(xì)胞凋亡,可能是通過抑制caspase3和促進(jìn)Bcl-2實(shí)現(xiàn)的。干擾AMPK能增加線粒體ROS的產(chǎn)生量。第二部分乏氧條件下AMPK-mTOR調(diào)節(jié)腦血管內(nèi)皮細(xì)胞自噬目的：觀察乏氧時(shí)腦血管內(nèi)皮細(xì)胞的自噬情況。研究乏氧促進(jìn)細(xì)胞自噬是通過HIF-1進(jìn)行的；研究AMPK與細(xì)胞凋亡的關(guān)系。研究mTOR對(duì)血管內(nèi)皮細(xì)胞的作用及是否受AMPK調(diào)控,并初步探討乏氧時(shí)腦血管內(nèi)皮中凋亡和自噬的關(guān)系。方法：將CMEC進(jìn)行乏氧處理,用免疫熒光觀察LC3蛋白的分布,Western blot檢測(cè)乏氧條件下CMEC的LC3 I、LC3 II亞型蛋白表達(dá),并觀察下調(diào)AMPK后期的表達(dá)情況。為研究乏氧促進(jìn)細(xì)胞自噬是通過HIF-1進(jìn)行的,腦血管內(nèi)皮細(xì)胞用HIF-1的抑制劑處理,用Westeren Blot檢HIF-1α磷酸化AMPK、LC3 Ⅰ、LC3 Ⅱ亞型蛋白的表達(dá)。用免疫沉淀檢測(cè)下調(diào)AMPK后,腦血管內(nèi)皮細(xì)胞中Bcl-2和Beclin的表達(dá)。為了研究AMPK與細(xì)胞凋亡的關(guān)系,我們檢測(cè)了在AMPK下調(diào)的腦血管內(nèi)皮細(xì)胞caspase-8活性及Bid的表達(dá)。為研究mTOR對(duì)血管內(nèi)皮細(xì)胞的作用及是否受AMPK調(diào)控,我們將乏氧培養(yǎng)的腦血管內(nèi)皮細(xì)胞AMPK下調(diào),Westernblot觀察腦血管內(nèi)皮細(xì)胞中AMPK、mTOR、P-mTOR、S6K、P-S6K的表達(dá)；為進(jìn)一步研究mTOR、AMPK和自噬之間的關(guān)系,我們用shRNA方法處理腦血管內(nèi)皮細(xì)胞,Western blot檢測(cè)mTOR、LC3表達(dá),用免疫熒光觀察細(xì)胞內(nèi)LC3的分布,免疫沉淀檢測(cè)腦血管內(nèi)皮細(xì)胞中Bcl-2和Beclin的表達(dá)。結(jié)果：乏氧時(shí),LC3蛋白重新分配到不同的點(diǎn),說明細(xì)胞正經(jīng)歷自噬,而對(duì)照組細(xì)胞則散布于細(xì)胞內(nèi),Western blot顯示乏氧條件下CMEC的LC3 II亞型蛋白水平增加,下調(diào)AMPK后,LC3 II亞型蛋白水平下降,證明乏氧條件下血管內(nèi)皮細(xì)胞自噬增加。HIF-1被抑制后磷酸化AMPK顯著降低,說明HIF-1可能通過活化AMPK誘導(dǎo)細(xì)胞自噬。乏氧時(shí),對(duì)照組血管內(nèi)皮細(xì)胞有較低的水平capase-8活性,而在AMPK下調(diào)細(xì)胞caspase-8活性增加,Bid表達(dá)增加,說明乏氧條件下,AMPK抑制腦血管內(nèi)皮細(xì)胞凋亡。下調(diào)腦血管內(nèi)皮細(xì)胞AMPK后,P-S6K水平增加,但總mTOR、S6K水平?jīng)]有明顯改變,說明AMPK抑制后,mTOR、S6K激活；抑制：mTOR表達(dá)后,CMEC的LC3 II亞型蛋白水平增加,mTOR表達(dá)下調(diào)細(xì)胞免疫熒光LC3染色,結(jié)果表明mTOR抑制后,細(xì)胞自噬能力增強(qiáng),證明了乏氧條件下,mTOR抑制腦血管內(nèi)皮細(xì)胞自噬。同時(shí)發(fā)現(xiàn)在mTOR表達(dá)下調(diào)細(xì)胞Bcl-2顯著增加,證明乏氧時(shí),腦血管內(nèi)皮細(xì)胞自噬增加后抑制凋亡。結(jié)論本課題證明了乏氧條件下,AMPK-mTOR有促進(jìn)腦血管內(nèi)皮細(xì)胞增殖、抑制其凋亡和促進(jìn)其自噬的功能,并探討了其分子機(jī)制,為臨床治療腦血管相關(guān)的疾病奠定了一定的理論基礎(chǔ)。
[Abstract]:Background and purpose of the brain is high blood flow, high oxygen consumption of the organs, the brain weight of only 2% of the body weight, blood flow and cardiac output accounted for about 15%, the oxygen consumption of the body about the oxygen consumption of 20%. but at the same time, the brain's energy reserves are almost only by providing oxygen and glucose of cerebral circulation aerobic metabolism, is highly dependent on cerebral circulation. Once complete cerebral ischemia occurred more than 5 minutes, brain cells would be an irreversible death, so the normal function of cerebral circulation is significant, especially in acute cerebral infarction and ischemic hypoxia, cerebral circulation function determines the development of the brain lesions and prognosis. The cerebral circulation is a highly specialized vascular bed, cerebral vascular endothelial cells in the brain plays an important role in the regulation of cerebral circulation. Vascular endothelial cells in some pathological conditions such as ischemia and hypoxia, often due to injury, Our previous study on cerebral ischemia and hypoxia are mainly in neurons, glial cells, neural stem cells, not much research on cerebral vascular endothelial cells. In addition to common cerebrovascular disease, many brain diseases are associated with ischemia and hypoxia, has important clinical significance and mechanism of hypoxia so function change the cerebral vascular endothelial cells during ischemia. The changes of cerebral hypoxia, vascular endothelial cell function mainly: proliferation, apoptosis, autophagy is the cell survival and endocrine change change, and change is the basis for survival, so this experiment of hypoxia on the proliferation of vascular endothelial cells, apoptosis and autophagy, and to explore its mechanism. Amp activated protein kinase (AMP-activated protein kinase, AMPK) is a metabolic sensor, the mammalian AMPK is ISO three dimer complex composed of three subunits, package The alpha subunit, P regulatory subunit gamma subunit.A and catalytic subunit containing a highly conserved serine threonine kinase domain, near the end of N- activation loop, Thr-172 phosphorylation on enzyme activity plays a key role; the P subunit has no catalytic activity, and intracellular AMPK alpha beta gamma complex the assembly and cell glycogen sensing gamma subunit; by sensing the intracellular ATP concentration of ADP and AMP in the regulation of enzyme activity. To keep the balance of energy metabolism through the activation of the AMPK pathway (ATP production) and inhibit the synthesis of metabolic pathways (ATP consumption) under the conditions of activation of.AMPK in poor nutritional conditions, effects of nutrient rich conditions loss of activity of.AMPK activated downstream including lipid and glucose metabolism, energy consumption, immune response, cell growth and polarity of.AMPK exists widely in human tissues, but the study of cerebral vascular endothelial cells is the mammalian target of rapamycin (Mam. Malian target of rapamycin, mTOR) is a serine threonine kinase regulates cell growth. The activation of AMPK mTOR activity and inhibit the activation of.MTOR needs to come from the nutrients (glucose, amino acids) and growth factor positive signal. In mammals, the mTORC1 complex (mTOR complex 1, mTORC1) is composed of four known subunits: Raptor, PRAS40, mLST8 and mTOR.mTORC1 are more sensitive to nutritional signals can be macrolide rapamycin bacteria quickly suppressed, control of cell growth, angiogenesis and metabolism. On the contrary, mTORC2 is not sensitive to nutrient signal, can not be the two known substrate inhibition of.MTORC1 is rapamycin soon 4EBP1 and p70 ribosomal S6 kinase. In addition to these growth signals to activate the]mTORC1 complex, through a variety of cellular stress rapidly inactivated, so as to ensure the cell from being damaged by a unique.MTORC1 complex The aspect is that it is dependent on nutrient utilization and performance of the kinase activity. In low oxygen conditions, cells activate a series of key pathways and adapt to survive, most of the way by the transcription factor hypoxia inducible factor 1 (Hypoxia inducible 1 factor, HIF-1) regulation, which depends on the stability and transcriptional activity in cells with oxygen the ability to control the]HIF-1 alpha as a signal to a great extent. The activation of HIF-1 is composed of HIF-1 alpha and HIF-1 beta two subunit composition of two heterologous dimers, HIF-1 alpha by oxygen concentration of fine adjustment and unstable, subunits and oxygen levels without.HIF-1 beta is a key molecule of hypoxia induced reaction of HIF-1 alpha, under hypoxic conditions, it is induced. Previous studies have shown that play an important role in the nervous system, but in the cerebral vascular endothelial cells AMPK with very little is known about this topic, we will use the separation of murine brain microvascular endothelial cells In the study of cerebral vascular endothelial cells under hypoxic conditions, including the proliferation and apoptosis of cerebral vascular endothelial cells, and to study the function of AMPK is carried out through the HIF-1. Autophagy is an important mechanism for the cell to maintain cell homeostasis, we will study the role and mechanism of.AMPK-mTOR in cerebral vascular endothelial cells autophagy in the first part under hypoxic conditions in cerebral vascular endothelial cells proliferation and induced mitochondria mediated apoptosis. AMPK pathway Objective: To study the expression of cerebral vascular cells in hypoxic conditions. To determine whether HIF-1 is involved in the activation of AMPK under hypoxic conditions. The study of AMPK under hypoxic conditions on the proliferation of vascular endothelial cell function AMPK and the mechanism of apoptosis. Methods: first isolated from murine brain microvascular endothelial cells (Cerebrovascular endothelial cells, CVEC), and then in hypoxia (1%02) and cultured under normoxic conditions, respectively. The observation of hypoxic 0,4,12 and 24 hours of MPK expression, used to detect the expression of AMPK Real time PCR. To determine whether HIF-1 is involved in the activation of AMPK under hypoxic conditions, we cultured vascular endothelial cells in mice under hypoxic conditions, and using the HIF-1 alpha inhibitor treated cells, the activity of AMPK cells was detected. AMPK the proliferation and apoptosis in cerebral vascular endothelial cells in the role of proliferation was detected by MTT in vascular endothelial cells under hypoxic conditions, to observe the proliferation of vascular endothelial cells by AMPK shRNA and AMPK inhibitor down regulated after AMPK. Flow cytometry was used to detect the apoptosis of vascular endothelial cells lack oxygen conditions, and AMPK shRNA AMPK was observed after downregulation of vascular endothelial cell apoptosis rate. At the same time with Western blot method to detect the cerebral vascular endothelial cells in Bcl-2, Cl-caspase3 expression by reactive oxygen detection reagent box under hypoxia reduced cerebral vascular AMPK Production of skin cell ROS. Results: we found that in mice cerebral vascular endothelial cells express AMPK alpha 2 and phosphorylated AMPK increased under hypoxic condition. When the anti HIF-1 alpha, phosphorylation of AMPK decreased, while AMPK decreased, that hypoxia can promote HIF-1 expression, promote AMPK the activation of.AMPK can promote the proliferation of.AMPK cells can inhibit cell apoptosis, possibly through inhibition of Caspase3 and promote the implementation of Bcl-2. AMPK can increase the amount of interference generated in mitochondrial ROS. The second part under hypoxic conditions AMPK-mTOR regulates autophagy in cerebral vascular endothelial cells Objective: cerebral vascular endothelial cell autophagy was observed in hypoxia. Hypoxia promotes research autophagy is carried out through the HIF-1; to study the relationship between AMPK and apoptosis. The effect of mTOR on vascular endothelial cells and is regulated by AMPK, and to investigate the apoptosis and autophagy of vascular endothelium of brain hypoxia . methods: CMEC for hypoxia treatment, observe the distribution of LC3 protein by immunofluorescence and Western blot detection of CMEC under hypoxic conditions by LC3 I, the expression of LC3 subtypes of II protein, and to observe the expression of AMPK down later. To study hypoxia promotes cell autophagy is carried out through the HIF-1, cerebral vascular endothelial cells treated with the inhibitors of HIF-1, Westeren Blot HIF-1 alpha phosphorylation of AMPK, LC3 I, the expression of LC3 II isoforms. Detection of down-regulation of AMPK by immunoprecipitation, the expression of Bcl-2 and Beclin in cerebral vascular endothelial cells. To study the relationship between AMPK and apoptosis, we examined the expression of AMPK in down cerebral vascular endothelial cells caspase-8 activity and Bid. To study the effects of mTOR on vascular endothelial cells and is regulated by AMPK, cerebral vascular endothelial cells under hypoxia AMPK we will cut, Westernblot observation of cerebral vascular endothelial cells in AMP K, mTOR, P-mTOR, S6K, P-S6K expression; for the further study of mTOR, the relationship between AMPK and autophagy, we treat cerebral vascular endothelial cells by shRNA method, Western blot detection of mTOR, LC3 expression, observe the distribution of LC3 in cells by immunofluorescence and immunoprecipitation to detect the expression of Bcl-2 and Beclin in cerebral vascular endothelial cells the results: hypoxia, LC3 protein re assigned to different points, indicating that cells undergoing autophagy, whereas the control group cells were scattered in the cytoplasm, Western blot showed that under hypoxic conditions CMEC LC3 subtype II protein level increased, decreased AMPK, LC3 subtype II protein level decreased, that under hypoxic conditions of vascular endothelial cells autophagy increased phosphorylation of AMPK.HIF-1 was inhibited significantly reduced, indicating that HIF-1 may through the activation of AMPK induced autophagy. The hypoxia control group, vascular endothelial cells have lower levels of capase-8 activity, whereas in AMPK To increase the activity of caspase-8 cells, increase the expression of Bid, that under hypoxic conditions, AMPK inhibited the apoptosis of cerebral vascular endothelial cells. Downregulation of cerebral vascular endothelial cells after AMPK, P-S6K levels increased, but the total mTOR did not change significantly the level of S6K, indicating that AMPK inhibited after mTOR, S6K activation; inhibition: the expression of mTOR, CMEC LC3 subtype II protein level increased mTOR expression by immunofluorescence LC3 staining, the results showed that mTOR inhibited, enhanced autophagy capacity, proved that under hypoxic conditions mTOR inhibition of cerebral vascular endothelial cells autophagy. At the same time found in mTOR expression Bcl-2 cells increased significantly, that of hypoxia, cerebral vascular endothelial cells autophagy increased after inhibition of apoptosis. Conclusion this study proved that under hypoxic conditions, AMPK-mTOR can promote the proliferation of vascular endothelial cells, inhibit apoptosis and promote the function of autophagy, and explore its molecular mechanism for the clinical treatment. It lays a theoretical basis for cerebrovascular diseases.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743

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