【摘要】：研究背景及目的血管鈣化,尤其是動(dòng)脈粥樣硬化鈣化是心腦血管疾病的重要因素之一。血管鈣化是一個(gè)由多種細(xì)胞啟動(dòng)并與骨發(fā)育類(lèi)似的、主動(dòng)的、高度可調(diào)控的、可預(yù)防和可逆轉(zhuǎn)的生物學(xué)過(guò)程。目前鈣化形成理論有骨形成蛋白調(diào)節(jié)、脂質(zhì)代謝紊亂、凋亡體基質(zhì)囊泡和氧化應(yīng)激等多種機(jī)制,但相關(guān)的分子機(jī)制尚不完全清楚。血管鈣化主要是中層血管平滑肌細(xì)胞(vascular smooth muscle cells,VSMCs)的鈣化。血管平滑肌細(xì)胞表達(dá)少量端粒酶(telomerase),有研究表明動(dòng)脈粥樣硬化斑塊VSMCs的端粒(telomere)長(zhǎng)度明顯短于正常血管VSMCs,端粒酶活性也明顯低,但端粒酶活性變化的調(diào)控機(jī)制及其在血管鈣化中的作用并不清楚。研究表明,NF-κB炎癥信號(hào)通路促進(jìn)骨形成蛋白(bone morphogenetic protein 2,BMP2)和成骨相關(guān)轉(zhuǎn)錄因子(runt-related transcription factor 2,RUNX2)的表達(dá),促進(jìn)VSMCs 化結(jié)節(jié)形成。研究發(fā)現(xiàn)核不均一核糖蛋白A1(heterogeneous nuclear ribonucleoproteinA1,hnRNPA1)可通過(guò)結(jié)合IκBα介導(dǎo)其發(fā)生蛋白酶體水解,促進(jìn)NF-κB入核,激活炎癥信號(hào)通路。hnRNPA1是hnRNPs家族中含量最為豐富的一類(lèi)蛋白,通過(guò)調(diào)控mRNA合成過(guò)程如mRNA轉(zhuǎn)錄、剪接、穩(wěn)定性以及mRNA從胞核到胞漿轉(zhuǎn)運(yùn)過(guò)程進(jìn)而調(diào)控靶基因的表達(dá)。我們的前期工作發(fā)現(xiàn),在血管平滑肌細(xì)胞由收縮型向合成型轉(zhuǎn)變的過(guò)程中,人端粒酶逆轉(zhuǎn)錄酶(human telomerase reverse transcriptase,hTERT)和hnRNPA1的表達(dá)均顯著上調(diào)。有文獻(xiàn)報(bào)道hnRNPA1可以延長(zhǎng)細(xì)胞端粒長(zhǎng)度,防止端粒過(guò)度損耗引發(fā)的細(xì)胞早衰。因此,本研究擬闡明hnRNPA1是否可以調(diào)控血管平滑肌細(xì)胞端粒酶活性和IκBα/NF-κB信號(hào)通路從而影響血管平滑肌細(xì)胞的鈣化過(guò)程。研究方法1.分離培養(yǎng)原代人臍動(dòng)脈血管平滑肌細(xì)胞(human umbilical artery smooth muscle cells,HUASMCs),構(gòu)建 pcDNA3.1-hnRNP A1真核表達(dá)載體并轉(zhuǎn)染 HUASMCs,通過(guò)端粒重復(fù)擴(kuò)增法(telomeric repeat amplification protocol,TRAP)、細(xì)胞增殖實(shí)驗(yàn)(MTS法)與流式細(xì)胞儀分別檢測(cè)hnRNP A1對(duì)HUASMCs端粒酶活性、增殖和凋亡功能的影響。2.建立HUASMCs鈣化模型,通過(guò)實(shí)時(shí)熒光定量PCR和Western blot法檢測(cè)NF-κB信號(hào)通路調(diào)控HUASMCs鈣化相關(guān)的各基因表達(dá),闡明hnRNP A1在血管平滑肌鈣化過(guò)程中的作用機(jī)制。研究結(jié)果1.體外培養(yǎng)HUASMCs結(jié)果表明,在HUASMCs由收縮型轉(zhuǎn)變?yōu)楹铣尚偷姆只^(guò)程中,端粒酶和hnRNP A1的表達(dá)水平均顯著上調(diào)。過(guò)表達(dá)hnRNP A1顯著上調(diào)端粒酶活性2.7倍,但對(duì)HUASMCs細(xì)胞的增殖和凋亡功能無(wú)顯著影響。2.通過(guò)建立HUASMCs鈣化模型結(jié)果表明,hnRNPA1可促進(jìn)HUASMCs細(xì)胞形成鈣化結(jié)節(jié),但其促進(jìn)鈣化的分子機(jī)制不是通過(guò)IκBα/NF-κB信號(hào)通路介導(dǎo),具體作用機(jī)制需要進(jìn)一步闡明。結(jié)論本研究發(fā)現(xiàn)端粒酶和hnRNP A1在血管平滑肌細(xì)胞由收縮型向合成型轉(zhuǎn)化的過(guò)程中表達(dá)上調(diào),過(guò)表達(dá)hnRNP A1顯著上調(diào)端粒酶活性,促進(jìn)動(dòng)脈粥樣硬化過(guò)程中的血管平滑肌細(xì)胞鈣化,但具體的分子機(jī)制有待于進(jìn)一步闡明。研究背景及目的動(dòng)脈粥樣硬化是衰老相關(guān)的炎性疾病。單核/巨噬細(xì)胞激活是動(dòng)脈粥樣硬化發(fā)生發(fā)展的關(guān)鍵核心,斑塊內(nèi)的巨噬細(xì)胞活動(dòng)可以引起活躍的炎癥反應(yīng)、纖維帽平滑肌細(xì)胞鈣化和脂質(zhì)堆積等,最終導(dǎo)致斑塊破裂,誘發(fā)猝死、急性心肌梗死、不穩(wěn)定型心絞痛和缺血性腦卒中。研究表明,在動(dòng)脈粥樣硬化形成的過(guò)程中端粒酶活性顯著上調(diào),然而有關(guān)端粒酶激活的分子機(jī)制尚不清楚。我們?cè)谇捌诠ぷ髦邪l(fā)現(xiàn)人頸動(dòng)脈粥樣硬化斑塊中巨噬細(xì)胞富集區(qū)域的人端粒酶逆轉(zhuǎn)錄酶(human telomerase reverse transcriptase,hTERT)表達(dá)顯著上調(diào),炎癥反應(yīng)活躍。此外,我們還發(fā)現(xiàn)在體外誘導(dǎo)單核細(xì)胞巨噬細(xì)胞分化的過(guò)程中,hTERT表達(dá)上調(diào)的同時(shí),一個(gè)特殊的microRNAs(miRNAs)分子,miR-216a的表達(dá)也顯著上調(diào)。已有研究提示,miR-216a在衰老內(nèi)細(xì)胞中表達(dá)上調(diào),抑制內(nèi)皮細(xì)胞自噬功能,參與巨噬細(xì)胞脂質(zhì)代謝,可能影響動(dòng)脈粥樣硬化性心血管疾病的發(fā)生發(fā)展。我們進(jìn)一步的實(shí)驗(yàn)研究結(jié)果提示miR-216a介導(dǎo)單核/巨噬細(xì)胞端粒酶激活,促進(jìn)巨噬細(xì)胞激活和炎癥反應(yīng)。本研究旨在探索miR-216a調(diào)控巨噬細(xì)胞端粒酶激活的分子機(jī)制,闡明其對(duì)巨噬細(xì)胞分化和功能的影響,為動(dòng)脈粥樣硬化性心血管疾病的治療提供新的理論依據(jù)。研究方法1.收集頸動(dòng)脈內(nèi)膜剝脫術(shù)后患者的頸動(dòng)脈斑塊組織,進(jìn)行免疫組化與免疫熒光染色,研究斑塊中單核/巨噬細(xì)胞與hTERT的共定位情況;2.體外佛波酯(phorbol-12-myristate-13-acetate,PMA)誘導(dǎo) THP1 單核細(xì)胞向巨噬細(xì)胞分化,探尋miR-216a與hTERT的表達(dá)變化,同時(shí)過(guò)表達(dá)及抑制miR-216a,研究miR-216a調(diào)控單核/巨噬細(xì)胞端粒酶激活的分子機(jī)制;3.采用ApoE-/-雄性小鼠進(jìn)行右頸動(dòng)脈串聯(lián)結(jié)扎術(shù),高脂飲食,構(gòu)建小鼠動(dòng)脈粥樣硬化模型,研究miR-216a是否可以通過(guò)調(diào)控單核/巨噬細(xì)胞激活來(lái)影響動(dòng)脈粥樣硬化斑塊的發(fā)展進(jìn)程。研究結(jié)果1.人頸動(dòng)脈粥樣硬化斑塊組織標(biāo)本的免疫組化和免疫熒光染色。結(jié)果顯示與正常血管比較,hTERT在斑塊內(nèi)巨噬細(xì)胞富集區(qū)域特異性表達(dá),端粒酶活性顯著升高。2.誘導(dǎo)THP-1細(xì)胞向巨噬細(xì)胞轉(zhuǎn)化發(fā)現(xiàn)miR-216a與hTERT的表達(dá)均明顯升高,進(jìn)一步研究表明miR-216a通過(guò)SMAD3/NF-κB信號(hào)通路調(diào)控單核/巨噬細(xì)胞端粒酶激活。3.小鼠動(dòng)脈粥樣硬化模型結(jié)果顯示,miR-216a促進(jìn)小鼠頸動(dòng)脈單核/巨噬細(xì)胞向M1型轉(zhuǎn)化,抑制其向M2型轉(zhuǎn)化,同時(shí)miR-216a還造成小鼠斑塊中Ⅲ型膠原減少,這與斑塊的穩(wěn)定性相關(guān)。結(jié)論本研究發(fā)現(xiàn)miR-216a可以通過(guò)SMAD3/NF-κB信號(hào)通路調(diào)控單核/巨噬細(xì)胞端粒酶激活,促進(jìn)巨噬細(xì)胞向M1型轉(zhuǎn)化及炎癥因子分泌,進(jìn)而促進(jìn)動(dòng)脈粥樣硬化斑塊發(fā)展進(jìn)程。
[Abstract]:BACKGROUND AND OBJECTIVE Vascular calcification, especially atherosclerotic calcification, is an important factor in cardiovascular and cerebrovascular diseases. Vascular calcification is an active, highly controllable, preventable and reversible biological process initiated by a variety of cells and similar to bone development. Vascular calcification is mainly the calcification of vascular smooth muscle cells (VSMCs). Vascular smooth muscle cells (VSMCs) express a small amount of telomerase. Studies have shown that atherosclerotic plaques. The telomere length of VSMCs was significantly shorter than that of normal VSMCs, and telomerase activity was also significantly lower, but the regulatory mechanism of telomerase activity and its role in vascular calcification were not clear. The expression of related transcription factor 2 (RUNX2) promotes the formation of VSMCs nodules. It is found that heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) can mediate the proteasome hydrolysis by binding to I kappa B alpha, promote the entry of NF-kappa B into the nucleus and activate the inflammatory signaling pathway. hnRNPA1 is the most abundant member of the hnRNPs family. A class of proteins that regulate the expression of target genes by regulating mRNA synthesis processes such as transcription, splicing, stability, and mRNA transport from nucleus to cytoplasm. Transriptase, hTERT) and hnRNPA1 expression were significantly up-regulated. It has been reported that hnRNPA1 can prolong telomere length and prevent premature senescence induced by telomere depletion. Therefore, this study is to clarify whether hnRNPA1 can regulate telomerase activity and I-kappa Balpha/NF-kappa B signaling pathway in vascular smooth muscle cells, thereby affecting vascular smooth muscle fineness. Methods 1. Human umbilical artery smooth muscle cells (HUASMCs) were isolated and cultured, and pcDNA3.1-hnRNP A1 eukaryotic expression vector was constructed and transfected into HUASMCs. The effect of hnRNP A1 on telomerase activity, proliferation and apoptosis of HUASMCs was detected by flow cytometry. 2. Calcification model of HUASMCs was established. The expression of genes related to calcification of HUASMCs was detected by real-time fluorescence quantitative PCR and Western blot. The mechanism of hnRNP A1 in the process of vascular smooth muscle calcification was elucidated. Results 1. HUASMCs cultured in vitro showed that the expression of telomerase and hnRNP A1 were significantly up-regulated during the process of HUASMCs differentiation from contractile to synthetic. Overexpression of hnRNP A1 significantly increased telomerase activity by 2.7 times, but had no significant effect on the proliferation and apoptosis of HUASMCs. 2. Calcification model of HUASMCs was established by overexpression of hnRNP A1. The results showed that hnRNPA1 could promote the formation of calcified nodules in HUASMCs, but the molecular mechanism of hnRNPA1 was not mediated by I-kappa Balpha/NF-kappa B signaling pathway, and the specific mechanism needed to be further clarified. Overexpression of hnRNP A1 significantly up-regulates telomerase activity and promotes calcification of vascular smooth muscle cells during atherosclerosis, but the specific molecular mechanisms need to be further clarified. Macrophage activity in the heart and plaque can cause active inflammation, calcification of fibrous cap smooth muscle cells and lipid accumulation, leading to plaque rupture, sudden death, acute myocardial infarction, unstable angina and ischemic stroke. However, the molecular mechanism of telomerase activation remains unclear. In our previous work, we found that the expression of human telomerase reverse transcriptase (hTERT) in the macrophage-rich region of human carotid atherosclerotic plaques was significantly up-regulated and the inflammation was active. In addition, we also found that monocytes were induced in vitro. In the process of macrophage differentiation, the expression of hTERT is up-regulated, and a special microRNAs (microRNAs) molecule, microRNAs-216a, is up-regulated. It has been suggested that microRNAs-216a may be up-regulated in aging cells, inhibit endothelial autophagy, participate in lipid metabolism of macrophages, and may affect atherosclerotic cardiovascular disease. Our further experimental results suggest that microRNA216a mediates telomerase activation in monocytes and macrophages, promotes macrophage activation and inflammation. The purpose of this study is to explore the molecular mechanism of microRNA216a regulating telomerase activation in macrophages, and to elucidate its effect on macrophage differentiation and function, which is called atherosclerosis. Methods 1. Carotid plaque tissues from patients after carotid endarterectomy were collected for immunohistochemistry and immunofluorescence staining to study the co-localization of monocyte/macrophage and hTERT in carotid plaque. 2. In vitro phorbol-12-myristate-13-acetate (PMA) induced THP1. Monocytes differentiate into macrophages, explore the changes of expression of microRNAs-216a and hTERT, overexpress and inhibit microRNAs-216a, and study the molecular mechanism of microRNAs regulating telomerase activation in monocytes/macrophages; 3. ApoE-/-male mice were used for right carotid artery ligation, high-fat diet, construction of atherosclerosis model, study of microRNAs-21. Results 1. Immunohistochemistry and immunofluorescence staining of human carotid atherosclerotic plaque tissue specimens. The results showed that hTERT was specifically expressed in the macrophage-rich region and telomerase activity in the plaque compared with normal blood vessels. The expression of microRNA-216a and hTERT was significantly increased in THP-1 cells induced to macrophage. Further studies showed that microRNA-216a regulated the telomerase activity of monocytes/macrophages through SMAD3/NF-kappa B signaling pathway. 3. Mice atherosclerosis model showed that microRNA-216a promoted carotid monocytes/macrophages to M1. Conclusion MicroRNA216a can regulate the telomerase activity of monocytes and macrophages through SMAD3/NF-kappa B signaling pathway, promote the transformation of macrophages to M1 and the secretion of inflammatory cytokines, thereby promoting the activation of monocytes and macrophages. The development of atherosclerotic plaque.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R543.5

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