Sirt去乙酰化酶在调节血管内皮细胞自噬反应中的角色
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摘要
随着世界人口的老龄化,心血管病以其高发病率成为影响人类健康的重要疾病之一。血管内皮细胞的正常功能对维持血管系统稳态、预防血管病变的发生具有重要的意义。内皮细胞功能受血液中层流剪切力(即血液流动对血管壁造成的水平方向切应力)的调节。生理状况下稳定的层流剪切力能够维持血管内皮正常功能和代谢,而非生理性的层流剪切力(过高、过低或震荡型的剪切力)可诱发血管内皮功能障碍,导致多种血管疾病(如动脉粥样硬化等)的发生。
细胞自噬是细胞在溶酶体系统作用下对己摄取的或原有的细胞组分进行自我消化的过程,是细胞在应激状态下维持细胞内大分子蛋白、细胞器循环和质量的主要方式。自噬对内皮细胞功能具有重要的调节作用：增强细胞对细菌感染的抵抗能力；提高细胞对饥饿、缺氧、高温以及高激素水平的耐受；对抗细胞凋亡等作用。但是,血液层流剪切力对内皮细胞自噬反应的调节尚未见报道。
自噬反应的激活受多条信号转导通路的调控(如胰岛素受体-雷帕霉素受体通路、脂多糖-AMPK通路、整联蛋白通路和钙离子通路等),研究表明细胞因子、糖基化产物和氧化低密度脂蛋白等多种因子参与内皮细胞自噬反应过程,但具体作用机制尚未阐明。自噬过程包括自噬小体(自噬相关蛋白Atg组成,双层膜为特征)和自噬溶酶体(自噬小体与溶酶体结合)形成。Sirtuin是NAD依赖的去乙酰化酶家族(Sirt1-Sirt7),在维持基因沉默、基因组的稳定、细胞代谢和延长细胞寿命过程中发挥重要作用。进一步研究发现某些SIRT家族成员(如Sirt1)可能参与细胞自噬反应调节,而血液层流剪切力可以影响内皮细胞中SIRT表达和功能。然而,日前Sirt在剪切力诱导的内皮细胞自噬反应中的作用和机制尚不明确。
本研究目的是明确血管内皮细胞中Sirt去乙酰化酶调节自噬功能的作用和机制,对于探讨血液层流剪切力参与血管疾病发生发展的生物学机制、指导临床靶向治疗具有重要的意义。
本论文包括了以下三部分研究内容：
第一部分：血液层流剪切力对内皮细胞自噬反应的影响
第二部分：Sirtl在介导内皮细胞自噬反应中作用及生物学机制
第三部分：Sirt2在内皮细胞氧化应激中作用的系统生物学研究
第一部分：血液层流剪切力对内皮细胞自噬反应的影响
研究目的
探讨剪切力是否能够调节内皮细胞的自噬功能；探讨剪切力是否通过改变细胞内氧化还原水平参与内皮细胞自噬功能的维持。
研究方法：
1、体外实验：采用M199培养基作为流体,用剪切力(20dyne/cm2)作用原代人脐静脉内皮(HUVECs)和人已细血管内皮细胞8小时后,将细胞分为Shear组(剪切力作用)和Static组(无剪切力作用),培养4小时。体内实验：24周龄的C57BL雄性小鼠给予右侧颈总动脉结扎48小时,左侧颈总动脉作为假手术对照。
2、免疫荧光检测HUVECs内Actin-beta的排列方向。自噬功能的检测包括下列方法：吖啶橙染色观察细胞内pH值的变化；DCFH-DA直接荧光标记观察细胞内ROS的变化；免疫荧光方法计数LC3的点状聚集,以LC3的点状聚集阳性细胞占总细胞的百分比评价自噬小体的形成；WB检调LC3的蛋白表达;RT-PCR检测自噬相关基因ATG5、Beclin-1(BECN1), MAP LC3的表达。用活性氧清除剂EUK-134预处理后,继续采用上述实验方法观察是否能逆转剪切力对自噬功能的调节。
3、人毛细血管内皮细胞转染pEGFP-LC3(?)质粒,共聚焦显微镜观察Shear对LC3点状聚集的影响,以LC3的点状聚集阳性细胞占总细胞的百分比表示;用EUK-134预处理后,仍采用上述方法观察是否能逆转剪切力对自噬的调节。
4、免疫组化观察C57BL小鼠双侧颈总动脉结扎部位至主动脉弓段LC3水平,透射电子显微镜观察双侧动脉内皮细胞内自噬小体的形成。
研究结果：
1、免疫荧光检测发现剪切力作用12小时能够使内皮细胞Actin-beta沿流体流动的方向排列,证明在体外成功建立了剪切力刺激细胞的模型。
2、Shear可以维持内皮细胞自噬反应：与Static组相比,Shear组LC3蛋白表达显著升高,LC3免疫荧光的点状聚集明显增多,细胞溶酶体酸化增强。
3、Shear对HUVECs自噬反应的调节是氧化-还原依赖的：与Static组相比,Shear组细胞内活性氧产生(DCFH-DA荧光)明显增多；活性氧清除剂EUK-134明显逆转内皮细胞自噬相关基因的高表达。
4、与Static组相比,Shear组LC3的点状聚集明显减少(EUK-134处理),表明过表达pEGFP-LC3的人毛细血管内皮细胞中剪切力对于的自噬反应的调节也是氧化-还原依赖的。
5、C57BL小鼠右侧颈总动脉结扎48小时后血管内皮LC3表达减少,血管内皮细胞内自噬小体减少。
结论：
1、剪切力能够维持内皮细胞自噬反应。
2、剪切力对内皮细胞自噬功能的维持是氧化-还原依赖的。
第二部分：Sirt1在介导内皮细胞自噬反应中的作用及生物学机制
研究目的
观察H202是否可以模拟剪切力对内皮细胞自噬功能的调节,明确Sirt1在对内皮细胞自噬功能维持中的作用,探讨Sirt1调节内皮细胞自噬反应的生物学机制。
研究方法：
1、SIRT1及细胞内自噬及相关信号蛋白的检测：H202处理HUVECs后,RT-PCR检测S1RT表达,WB检测Sirt、LC3、mTOR、p-mTOR、ULK、p-ULK表达：Sirt1抑制剂Ex-527预处理H202刺激的内皮细胞,RT-PCR检测自噬相关基因(LC3、ATG5、Beclin-1)(?)勺表达。siRNA技术敲除Sirt1后,WB检测LC3表达,siRNA技术敲除人毛细血管内皮细胞Sirt1后,免疫荧光计数LC3的点状聚集,并计算其占总细胞的百分比；剪切力模型中,用Ex-527处理转染pEGFP-LC3质粒的人毛细血管内皮细胞,共聚焦显微镜观察LC3的点状聚集阳性细胞,并计算其占总细胞的百分比。在转染Flag-SIRT1质粒或白藜芦醉作用后的内皮细胞中,WB检测LC3表达。
2、Sirtl-Foxola信号通路的检测：过表达Foxola的内皮细胞给予H2O2、白藜芦醇刺激后,免疫共沉淀法检测Foxola的乙酰化水、内皮细胞分别转染固有活性的Foxola的质粒和野生型Foxola的质粒后,白藜芦醇继续作用后,RT-PCR法检测自噬相关基因(LC3、ATG5、Belcin-1)表达变化。RT-PCR法检测Foxola siRNA与Flag-SIRT1共转染对自噬相关基因(LC3、ATG5、Belcin-1)表达的影响。
3、免疫荧光法观察转染Flag-SIRT1质离后,Foxola在HUVECs中的核转位,RT-PCR检测Foxola靶基因和自噬相关基因(LC3、ATG5、Belcin-1)表达变化。研究结果：
1、RT-PCR检测到内皮细胞S1RT1-7农达。
2、剪切力增强内皮细胞SIRT1的表达。
3、H2O2对抑制自噬反应的mTOR通路无显著影响：H2O2处理HUVECs后,mTOR、p-mTOR、ULK、p-ULK表达无显著变化。
4、H2O2上调内皮细胞SIRT1的表达：H2O2以时间依赖方式促进内皮细胞SIRT1基因和蛋白表达。
5、Sirtl激活剂白藜醇能够增强内皮细胞自噬反应：白藜芦醇以时间依赖方式促进内皮细胞Sirt1、LC3表达。
6、百藜芦醇上调过表达Foxo1a的内皮细胞中自噬相关基因的转录表达。
7、H2O2、白藜芦醇降低了过表达Foxo1a的内皮细胞中Foxo1a的乙酰化表达。
8、Flag-SIRT1上调了自噬关基因的转录表达。
9、Sirt1抑制剂能够抑制内皮细胞自噬反应：Sirt1抑制剂Ex-527预处理HUVECs后,H202对HUVECs自噬相关基因在1nRNA水平上的升高作用被抑制。用Ex-527处理转染pEGFP-LC3质粒的人毛细血管内皮细胞,Shear组LC3的点状聚集阳性细胞占总细胞的百分比较Static组升高的作用被抑制。
10、Sirtl的siRNA能够抑制内皮细胞自噬反应：Sirtl的siRNA转染HUVECs和人毛细血管内皮细胞后,H202继续作用后LC3表达降低,LC3的点状聚集减少。
11、Sirtl和自噬反应对氧化应激状态下内皮细胞活性的影响：Ex-527、自噬反应抑制剂3-MA预处理降低了内皮细胞的活力及对H202的耐受。
12、Sirtl对Foxola在细胞内定位的作用：分别转染Flag-SIRT1质粒和应用白藜芦醇后,Foxola在HUVECs中发生核转位；同时,Flag-SIRT1也提高了自噬相关基因的转录水平。
13、Foxola过表达对内皮细胞自噬反应的影响：内皮细胞转染带活性Foxola的质粒和野生型Foxola的质粒后,自噬相关基因MAP_LC3转录水平明显升高。
14、Foxola对过表达Flag-SIRT1的内皮细胞自噬反应的影响：共转染Foxola的siRNA与Flag-SIRT1质粒后,HUVECs自噬相关基因表达无显著变化。
结论：
Sirt1介导剪切力诱发的自噬反应,Sirtl通过去乙酰化Foxola调节自噬相关基因表达是Sirt1调节内皮细胞自噬反应的机制之一。
第三部分SIRT2在内皮细胞氧化应激中作用的系统生物学研究
研究目的：
探讨内皮细胞Sirt2在氧化应激中的作用。
研究方法：
采用基因芯片和RT-PCR实验验证原代人脐静脉内皮细胞Sirt2沉默后,氧化应激作用下基因表达的变化。MTS法检测内皮细胞活性。
研究结果：
1、H202诱导内皮细胞的氧化应激反应
2、氧化应激作用下SIRT2表达升高。
3、Sirt2沉默对内皮细胞氧化应激状态下基因转录组的影响：Sirt2沉默后有340个基因的表达发生变化,这些基因主要参与肌动蛋白结合和细胞代谢的生理过程。
4、Sirt2敏感基功能的生物信息学分析：转染Sirt2的siRNA调节的基因参与跨膜受体蛋白丝氨酸/苏氨酸激酶信号、铁离子运输、蛋白质的运输和定位等。这些基因和相关的功能在根大程度上与转染Sirt1的siRNA后的关功能是不重叠的。
5、氧化应激状态下AGK2(抑制Sirt2)对内皮细胞活性起保护作用。
结论：
Sirt2去乙酰化在内皮细胞氧化应激中起到重要作用,与Sirt1作用不同,内皮细胞Sirt2的抑制可能起到对细胞活性和生存的保护作用。
Cardiovascular disorder has become one of the major diseases affecting human health with its high incidence as world's population is aging. The vascular endothelial cell homeostasis is vital to maintain vascular system stability and to prevent vascular disease. Endothelial cell function is regulated by blood flow shear stress (that is the blood flow force of vascular wall caused by the horizontal shear force). Physiological and steady shear force can maintain vascular endothelial normal physiological functions and metabolism. However, non physiological shear force (too high, too low shear stress or shock type) can induce endothelial dysfunction and lead to a variety of vascular disease.
Cell autophagy is a self digestion process involving degradation of the endogenous cell components in lysosomal system. Autophagy reaction is the main pathway of preventing from stress stimulation and maintaining the quality of macromolecular proteins and organelles in cell cycle under stress in mammalian cells. In endothelial cells, the autophagic response plays an important role in cell function regulation. Autophagy can protect cells against bacteria infection, improve the resistance capacity of endothelial cells in starvation and hypoxia, high temperature and hormone, and protect from cell apoptosis. However, whether blood flow shear stress can regulate autophagy reaction in endothelial cells remains unknown.
The initial activation of autophagy is triggered by multiple signaling pathways, such as the insulin receptor rapamycin receptor pathway. Adenosine Monophosphate Activated Protein Kinase (AMPK) pathway, the integrin protein and calcium-mediated signaling pathways. Cytokines, glycosylation and oxidized low density lipoprotein are involved in autophagy reaction of endothelial cells. The mechanisms of endothelial autophagy are not totally clear. Autophagy process includs Atg protein conjunction, autophagosome formation characterized by double membrane, cytolysosome and lysosomes form autophagy-lysosome and the degradation of the contents. Sirtuin is a nicotinamide adenine dcnucleotids (NAD) dependent dacetylation enzyme family (Sirtl-Sirt7). Sirt maintains gene silencing, chromosome stability, cell metabolism and cell life. It has been found that some members of the Sirt family, such as Sirtl may participate in regulating cell autophagy reaction. Evidence reveals that shear force can influence S1RT1expression in endothelial cells. However. It is unclear whether SIRT protein participates in cell autophagy regulated by shear stress.
In contrast to Sirtl, the biological functions of Sirt2in endothelial cells remain unknown. Therefore, we explored the role of Sirt2under oxidative stress by examining global gene expression in this study.
In this thesis we aimed to clarify the role of Sirt in regulation of autopahgy in endothelial cells and the mechanisms involved in the process.
The whole thesis includes3parts:
Part Ⅰ:Effects of shear stress on autophagy in endothelial cells
Part Ⅱ:The role of Sirtl in regulating autophagy in endothelial cells
Part Ⅲ:Global gene expression study of Sirt2in endothelial cells under oxidative stress
Part I:Effects of shear stress on endothelial cell autophagy
Objective:
To explore how shear stress regulates autophagy in endothelial cells and whether this effect is redox dependent.
Methods:
1. In vitro studies were performed as follows:we maintained full name (HUVECs) under20dyne/cm2flow to mimics physiological blood How status and0dyne/cm2flow as the static status. M199medium was used as a fluid buffer in both statuses. The24-week-old C57BL male mice were used to establish the physiological blood flow shear blood flow and static blood flow model as follows: mice underwent the right common carotid artery distal ligation and left carotid artery sham operation for48hours.
2. Immune fluorescence was used to determine Actin-beta arrangement direction in HUVECs. Autophagy evaluation included the following parts:firstly, Acridine orange staining to observe intracellular pH level; secondly, direct DCFH-DA fluorescence to examine intracellular full (ROS) change; immune fluorescence to count LC3punctate aggregation (the percentage of positive LC3punctation gathered cells of the total cell); Western blot to detect LC3protein level; PCR to measure autophagy related genes expression including ATG5, Beclin-1and MAP_LC3. Moreover, EUK-134pretreatment was given to evaluate whether the antioxidant compound can reverse shear induced autophagy in endothelial cells.
3. We counted LC3punctation aggregation percentage by confocal microscope in human capillary endothelial cells with pEGFP-LC3plasmid transfection. EUK-134pretreatment was also given to observe whether it can reverse the regulation of shear on autophagy.
4. LC3in the carotid artery ligation of C57BL mice was observed by immunohistochemical staining. The formation of autophagosome in the bilateral endothelial cells was counted by transmission electron microscope.
Results:
1. Shear stress induced alignment of actin fibers in endothelial cells along the direction of fluid flow compared to static condition, which confirmed that an in vitro shear stress model was successfully established.
2. Compared to static group, total LC3expression under shear stress was significantly increased as measured by western blotting. LC3punctation significantly increased as measured by immune fluorescence staining. pH value reduced in endothelial cells in shear group compared to static group as shown by acridine orange staining.3. Compared to static flow, DCFH-DA fluorescence increased significantly under shear status. It is confirmed that shear maintained endothelial autophagy related genes at the transcriptional level by PCR, and the effect can be reversed by pretreatment of EUK-134.
4. In human capillary endothelial cells transfected with pEGFP-LC3plasmid, it was revealed that shear group also maintained LC3punctate aggregation as measured by fluorescence microscope, which can be reversed with EUK-134pretreatment. It was found that4-hr H2O2treatment in HUVECs, increased significantly LC3fluorescence punctation intracellular aggregation.
5. It was also found that LC3expression reduced48h after carotid artery ligation. The number of autophagosome in endothelial cell cytoplasm reduced after carotid artery ligation.
Conclusions:
Shear stress maintains autophagy process in endothelial cells, which is in a cellular redox-dependent manner.
Part II SIRTl is involved in shear stress-induced autophagy
Ohjective:
To investigate if H2O2can mimic shear stress-regulated endothelial cell autophagy; to confirm if SIRT1is involved in shear-autophagy signaling pathway; to study the mechanism of SIRT1regulation of endothelial cell autophagy.
Methods:
1. The detection of SIRT1and autophagy related genes and proteins expression. SIRTl, ATG5, Bed in-1, MAP LC3expression was measured by PCR;LC3, mTOR, p-mTOR, ULK, p-ULK expression was measured by western blot in cells with or without SIRT1inhibitor Ex-527prctreatment before H2O2. LC3expression and its punctation aggregation were measured in Sirtl的siRNA transfected HUVECs and human capillary endothelial cells, respectively. LC3punctation was measured directly in pEGFP-LC3ovcrexpressing human microvascular endothelial cell line, which were pretreated with shear stress and/or Ex-527. Total LC3protein or LC3H/LC31was detected by western blot in pc I)NA3Flag-SIRT1transfected or resveratrol-treated cells
2. Sirtl-Foxola signaling detection:Sirtl and Foxola binding or Foxola aeetylation level were detected in Foxola-transfected HUVECs which were treated with H1O2and resveratrol. The effect of resveratrol treatment after pc DNA3Flag-Foxol a-AAA and wild type Foxo1a transfection on autophagy related gene expression was detected by PCR as well as the effect of co-transfected with the FOXO1A siRNA (Si-FOXO1A) and Flag-SIRT1.
3. Foxola nuclear location was observed in Flag-SIRT1, resveratrol treated HUVECs by immunofluorescence; Foxo1a target genes, and autophagy related gene expression was detected by PCR.
Results:
1. SIRT1-7were expressed in endothelial cells as revealed by gel electrophoresis of PCR products.
2. Shear stress induced SIRT1expression in endothelial cells.
3. There were no obvious changes of mTOR, p-mTOR, ULK, p-ULK in H2O2treated HUVECs.
4. ROS increased SIRT1gene expression. Both SIRT1gene and protein expression was increased in HUVECs after H2O2treatment in a time-dependent manner.
5. Resveratrol, an agonist of Sirt1, can enhance autophagy.
6. Resveratrol treatment increased ATG5, Beclin-1, and MAP_LC3mRNA expression in constitutively active Foxo1a transfected cells.
7. In Flag-FKHR transfected HUVECs, H2O2and resveratrol increased Foxo1a deacetylation level.
8. Flag-SIRT1overexpression increased the transeriptional level of autophagy related genes.
9. Sirtl inhibitor Ex-527inhibited autophagy:Increased ATG5, Beclin-1, and MAP_LC3mRNA levels induced by H2O2were reversed with Ex-527pretreatment. LC3punctatation decreased in pEGFP-LC3transfected human capillary vascular endothelial cells which underwent Ex-527pretreatment, in shear flow group.
10. Sirt1knock down also inhibited autophagy. LC3punctation aggregation was reduced in human capillary endothelial cells by Sirt1knocking down.
11. Both Ex-527and3-MA pretreatment in HUVECs reduced endothelial cells survival after oxidative stress challenge.
12. Sirt1effects on Foxola localization in HUVECs. SIRT1overexpression transfection and resveratrol treatment triggered nuclear localization of Foxola. SIRT1overexpression increased autophagy related gene transcription levels.
13. FOXO1A over expression in endothelial cells affects autophagy:MAP_LC3 significantly increased after overexpression of wild type or constitutively active Foxola.
14. FOXO1A knock down reversed A TG5. Bed in-1, and MAP LC3mRNA upregulation induced by SIRT1overexpression in HUVECs.
Conclusion:
Sirtl mediates shear-induced autophagy in endothelial cells. Sirtl regulates autophagy by Foxola deacetylation in endothelial cells.
Part Ⅲ Systemic biology study on the role of Sirt2in endothelial cells under oxidative stress
Objective:
To investigate the role of endothelial NAD+-dependcnt deacetylase Sirt2in endothelial cells under oxidative stress.
Methods:
Global gene expression changes were examined using cDNAmicroarray and PCR after Sirt2knocking down in primary HUVECs under oxidative stress. MTS assay was used to measure endothelial cell activity.
Results:
1. H2O2treatment induced oxidative stress response.
2. SIRT2expression was increased under oxidative stress.
3. Sirt2knocking down changed expression of340genes, which are mainly involved in cellular processes including actin binding, cellular amino acid metabolic process, transmembranc receptor protein scrine/threoninc kinase signaling, ferrous iron transport, protein transport and localization, cell morphogenesis, and functions associated with endosome membrane and the trans-Golgi network.
4. These above genes and associated functions were largely non-overlapping with those regulated by Sirtl knocking down.
5. Pharmacological inhibition of Sirt2attenuated oxidant-induced cell toxicity in endothelial cells.
Conclusions:Sirt2is functionally important in endothelial cells under oxidative stress, and it may have a primarily distinct role from Sirtl.
细胞自噬是细胞在溶酶体系统作用下对己摄取的或原有的细胞组分进行自我消化的过程,是细胞在应激状态下维持细胞内大分子蛋白、细胞器循环和质量的主要方式。自噬对内皮细胞功能具有重要的调节作用：增强细胞对细菌感染的抵抗能力；提高细胞对饥饿、缺氧、高温以及高激素水平的耐受；对抗细胞凋亡等作用。但是,血液层流剪切力对内皮细胞自噬反应的调节尚未见报道。
自噬反应的激活受多条信号转导通路的调控(如胰岛素受体-雷帕霉素受体通路、脂多糖-AMPK通路、整联蛋白通路和钙离子通路等),研究表明细胞因子、糖基化产物和氧化低密度脂蛋白等多种因子参与内皮细胞自噬反应过程,但具体作用机制尚未阐明。自噬过程包括自噬小体(自噬相关蛋白Atg组成,双层膜为特征)和自噬溶酶体(自噬小体与溶酶体结合)形成。Sirtuin是NAD依赖的去乙酰化酶家族(Sirt1-Sirt7),在维持基因沉默、基因组的稳定、细胞代谢和延长细胞寿命过程中发挥重要作用。进一步研究发现某些SIRT家族成员(如Sirt1)可能参与细胞自噬反应调节,而血液层流剪切力可以影响内皮细胞中SIRT表达和功能。然而,日前Sirt在剪切力诱导的内皮细胞自噬反应中的作用和机制尚不明确。
本研究目的是明确血管内皮细胞中Sirt去乙酰化酶调节自噬功能的作用和机制,对于探讨血液层流剪切力参与血管疾病发生发展的生物学机制、指导临床靶向治疗具有重要的意义。
本论文包括了以下三部分研究内容：
第一部分：血液层流剪切力对内皮细胞自噬反应的影响
第二部分：Sirtl在介导内皮细胞自噬反应中作用及生物学机制
第三部分：Sirt2在内皮细胞氧化应激中作用的系统生物学研究
第一部分：血液层流剪切力对内皮细胞自噬反应的影响
研究目的
探讨剪切力是否能够调节内皮细胞的自噬功能；探讨剪切力是否通过改变细胞内氧化还原水平参与内皮细胞自噬功能的维持。
研究方法：
1、体外实验：采用M199培养基作为流体,用剪切力(20dyne/cm2)作用原代人脐静脉内皮(HUVECs)和人已细血管内皮细胞8小时后,将细胞分为Shear组(剪切力作用)和Static组(无剪切力作用),培养4小时。体内实验：24周龄的C57BL雄性小鼠给予右侧颈总动脉结扎48小时,左侧颈总动脉作为假手术对照。
2、免疫荧光检测HUVECs内Actin-beta的排列方向。自噬功能的检测包括下列方法：吖啶橙染色观察细胞内pH值的变化；DCFH-DA直接荧光标记观察细胞内ROS的变化；免疫荧光方法计数LC3的点状聚集,以LC3的点状聚集阳性细胞占总细胞的百分比评价自噬小体的形成；WB检调LC3的蛋白表达;RT-PCR检测自噬相关基因ATG5、Beclin-1(BECN1), MAP LC3的表达。用活性氧清除剂EUK-134预处理后,继续采用上述实验方法观察是否能逆转剪切力对自噬功能的调节。
3、人毛细血管内皮细胞转染pEGFP-LC3(?)质粒,共聚焦显微镜观察Shear对LC3点状聚集的影响,以LC3的点状聚集阳性细胞占总细胞的百分比表示;用EUK-134预处理后,仍采用上述方法观察是否能逆转剪切力对自噬的调节。
4、免疫组化观察C57BL小鼠双侧颈总动脉结扎部位至主动脉弓段LC3水平,透射电子显微镜观察双侧动脉内皮细胞内自噬小体的形成。
研究结果：
1、免疫荧光检测发现剪切力作用12小时能够使内皮细胞Actin-beta沿流体流动的方向排列,证明在体外成功建立了剪切力刺激细胞的模型。
2、Shear可以维持内皮细胞自噬反应：与Static组相比,Shear组LC3蛋白表达显著升高,LC3免疫荧光的点状聚集明显增多,细胞溶酶体酸化增强。
3、Shear对HUVECs自噬反应的调节是氧化-还原依赖的：与Static组相比,Shear组细胞内活性氧产生(DCFH-DA荧光)明显增多；活性氧清除剂EUK-134明显逆转内皮细胞自噬相关基因的高表达。
4、与Static组相比,Shear组LC3的点状聚集明显减少(EUK-134处理),表明过表达pEGFP-LC3的人毛细血管内皮细胞中剪切力对于的自噬反应的调节也是氧化-还原依赖的。
5、C57BL小鼠右侧颈总动脉结扎48小时后血管内皮LC3表达减少,血管内皮细胞内自噬小体减少。
结论：
1、剪切力能够维持内皮细胞自噬反应。
2、剪切力对内皮细胞自噬功能的维持是氧化-还原依赖的。
第二部分：Sirt1在介导内皮细胞自噬反应中的作用及生物学机制
研究目的
观察H202是否可以模拟剪切力对内皮细胞自噬功能的调节,明确Sirt1在对内皮细胞自噬功能维持中的作用,探讨Sirt1调节内皮细胞自噬反应的生物学机制。
研究方法：
1、SIRT1及细胞内自噬及相关信号蛋白的检测：H202处理HUVECs后,RT-PCR检测S1RT表达,WB检测Sirt、LC3、mTOR、p-mTOR、ULK、p-ULK表达：Sirt1抑制剂Ex-527预处理H202刺激的内皮细胞,RT-PCR检测自噬相关基因(LC3、ATG5、Beclin-1)(?)勺表达。siRNA技术敲除Sirt1后,WB检测LC3表达,siRNA技术敲除人毛细血管内皮细胞Sirt1后,免疫荧光计数LC3的点状聚集,并计算其占总细胞的百分比；剪切力模型中,用Ex-527处理转染pEGFP-LC3质粒的人毛细血管内皮细胞,共聚焦显微镜观察LC3的点状聚集阳性细胞,并计算其占总细胞的百分比。在转染Flag-SIRT1质粒或白藜芦醉作用后的内皮细胞中,WB检测LC3表达。
2、Sirtl-Foxola信号通路的检测：过表达Foxola的内皮细胞给予H2O2、白藜芦醇刺激后,免疫共沉淀法检测Foxola的乙酰化水、内皮细胞分别转染固有活性的Foxola的质粒和野生型Foxola的质粒后,白藜芦醇继续作用后,RT-PCR法检测自噬相关基因(LC3、ATG5、Belcin-1)表达变化。RT-PCR法检测Foxola siRNA与Flag-SIRT1共转染对自噬相关基因(LC3、ATG5、Belcin-1)表达的影响。
3、免疫荧光法观察转染Flag-SIRT1质离后,Foxola在HUVECs中的核转位,RT-PCR检测Foxola靶基因和自噬相关基因(LC3、ATG5、Belcin-1)表达变化。研究结果：
1、RT-PCR检测到内皮细胞S1RT1-7农达。
2、剪切力增强内皮细胞SIRT1的表达。
3、H2O2对抑制自噬反应的mTOR通路无显著影响：H2O2处理HUVECs后,mTOR、p-mTOR、ULK、p-ULK表达无显著变化。
4、H2O2上调内皮细胞SIRT1的表达：H2O2以时间依赖方式促进内皮细胞SIRT1基因和蛋白表达。
5、Sirtl激活剂白藜醇能够增强内皮细胞自噬反应：白藜芦醇以时间依赖方式促进内皮细胞Sirt1、LC3表达。
6、百藜芦醇上调过表达Foxo1a的内皮细胞中自噬相关基因的转录表达。
7、H2O2、白藜芦醇降低了过表达Foxo1a的内皮细胞中Foxo1a的乙酰化表达。
8、Flag-SIRT1上调了自噬关基因的转录表达。
9、Sirt1抑制剂能够抑制内皮细胞自噬反应：Sirt1抑制剂Ex-527预处理HUVECs后,H202对HUVECs自噬相关基因在1nRNA水平上的升高作用被抑制。用Ex-527处理转染pEGFP-LC3质粒的人毛细血管内皮细胞,Shear组LC3的点状聚集阳性细胞占总细胞的百分比较Static组升高的作用被抑制。
10、Sirtl的siRNA能够抑制内皮细胞自噬反应：Sirtl的siRNA转染HUVECs和人毛细血管内皮细胞后,H202继续作用后LC3表达降低,LC3的点状聚集减少。
11、Sirtl和自噬反应对氧化应激状态下内皮细胞活性的影响：Ex-527、自噬反应抑制剂3-MA预处理降低了内皮细胞的活力及对H202的耐受。
12、Sirtl对Foxola在细胞内定位的作用：分别转染Flag-SIRT1质粒和应用白藜芦醇后,Foxola在HUVECs中发生核转位；同时,Flag-SIRT1也提高了自噬相关基因的转录水平。
13、Foxola过表达对内皮细胞自噬反应的影响：内皮细胞转染带活性Foxola的质粒和野生型Foxola的质粒后,自噬相关基因MAP_LC3转录水平明显升高。
14、Foxola对过表达Flag-SIRT1的内皮细胞自噬反应的影响：共转染Foxola的siRNA与Flag-SIRT1质粒后,HUVECs自噬相关基因表达无显著变化。
结论：
Sirt1介导剪切力诱发的自噬反应,Sirtl通过去乙酰化Foxola调节自噬相关基因表达是Sirt1调节内皮细胞自噬反应的机制之一。
第三部分SIRT2在内皮细胞氧化应激中作用的系统生物学研究
研究目的：
探讨内皮细胞Sirt2在氧化应激中的作用。
研究方法：
采用基因芯片和RT-PCR实验验证原代人脐静脉内皮细胞Sirt2沉默后,氧化应激作用下基因表达的变化。MTS法检测内皮细胞活性。
研究结果：
1、H202诱导内皮细胞的氧化应激反应
2、氧化应激作用下SIRT2表达升高。
3、Sirt2沉默对内皮细胞氧化应激状态下基因转录组的影响：Sirt2沉默后有340个基因的表达发生变化,这些基因主要参与肌动蛋白结合和细胞代谢的生理过程。
4、Sirt2敏感基功能的生物信息学分析：转染Sirt2的siRNA调节的基因参与跨膜受体蛋白丝氨酸/苏氨酸激酶信号、铁离子运输、蛋白质的运输和定位等。这些基因和相关的功能在根大程度上与转染Sirt1的siRNA后的关功能是不重叠的。
5、氧化应激状态下AGK2(抑制Sirt2)对内皮细胞活性起保护作用。
结论：
Sirt2去乙酰化在内皮细胞氧化应激中起到重要作用,与Sirt1作用不同,内皮细胞Sirt2的抑制可能起到对细胞活性和生存的保护作用。
Cardiovascular disorder has become one of the major diseases affecting human health with its high incidence as world's population is aging. The vascular endothelial cell homeostasis is vital to maintain vascular system stability and to prevent vascular disease. Endothelial cell function is regulated by blood flow shear stress (that is the blood flow force of vascular wall caused by the horizontal shear force). Physiological and steady shear force can maintain vascular endothelial normal physiological functions and metabolism. However, non physiological shear force (too high, too low shear stress or shock type) can induce endothelial dysfunction and lead to a variety of vascular disease.
Cell autophagy is a self digestion process involving degradation of the endogenous cell components in lysosomal system. Autophagy reaction is the main pathway of preventing from stress stimulation and maintaining the quality of macromolecular proteins and organelles in cell cycle under stress in mammalian cells. In endothelial cells, the autophagic response plays an important role in cell function regulation. Autophagy can protect cells against bacteria infection, improve the resistance capacity of endothelial cells in starvation and hypoxia, high temperature and hormone, and protect from cell apoptosis. However, whether blood flow shear stress can regulate autophagy reaction in endothelial cells remains unknown.
The initial activation of autophagy is triggered by multiple signaling pathways, such as the insulin receptor rapamycin receptor pathway. Adenosine Monophosphate Activated Protein Kinase (AMPK) pathway, the integrin protein and calcium-mediated signaling pathways. Cytokines, glycosylation and oxidized low density lipoprotein are involved in autophagy reaction of endothelial cells. The mechanisms of endothelial autophagy are not totally clear. Autophagy process includs Atg protein conjunction, autophagosome formation characterized by double membrane, cytolysosome and lysosomes form autophagy-lysosome and the degradation of the contents. Sirtuin is a nicotinamide adenine dcnucleotids (NAD) dependent dacetylation enzyme family (Sirtl-Sirt7). Sirt maintains gene silencing, chromosome stability, cell metabolism and cell life. It has been found that some members of the Sirt family, such as Sirtl may participate in regulating cell autophagy reaction. Evidence reveals that shear force can influence S1RT1expression in endothelial cells. However. It is unclear whether SIRT protein participates in cell autophagy regulated by shear stress.
In contrast to Sirtl, the biological functions of Sirt2in endothelial cells remain unknown. Therefore, we explored the role of Sirt2under oxidative stress by examining global gene expression in this study.
In this thesis we aimed to clarify the role of Sirt in regulation of autopahgy in endothelial cells and the mechanisms involved in the process.
The whole thesis includes3parts:
Part Ⅰ:Effects of shear stress on autophagy in endothelial cells
Part Ⅱ:The role of Sirtl in regulating autophagy in endothelial cells
Part Ⅲ:Global gene expression study of Sirt2in endothelial cells under oxidative stress
Part I:Effects of shear stress on endothelial cell autophagy
Objective:
To explore how shear stress regulates autophagy in endothelial cells and whether this effect is redox dependent.
Methods:
1. In vitro studies were performed as follows:we maintained full name (HUVECs) under20dyne/cm2flow to mimics physiological blood How status and0dyne/cm2flow as the static status. M199medium was used as a fluid buffer in both statuses. The24-week-old C57BL male mice were used to establish the physiological blood flow shear blood flow and static blood flow model as follows: mice underwent the right common carotid artery distal ligation and left carotid artery sham operation for48hours.
2. Immune fluorescence was used to determine Actin-beta arrangement direction in HUVECs. Autophagy evaluation included the following parts:firstly, Acridine orange staining to observe intracellular pH level; secondly, direct DCFH-DA fluorescence to examine intracellular full (ROS) change; immune fluorescence to count LC3punctate aggregation (the percentage of positive LC3punctation gathered cells of the total cell); Western blot to detect LC3protein level; PCR to measure autophagy related genes expression including ATG5, Beclin-1and MAP_LC3. Moreover, EUK-134pretreatment was given to evaluate whether the antioxidant compound can reverse shear induced autophagy in endothelial cells.
3. We counted LC3punctation aggregation percentage by confocal microscope in human capillary endothelial cells with pEGFP-LC3plasmid transfection. EUK-134pretreatment was also given to observe whether it can reverse the regulation of shear on autophagy.
4. LC3in the carotid artery ligation of C57BL mice was observed by immunohistochemical staining. The formation of autophagosome in the bilateral endothelial cells was counted by transmission electron microscope.
Results:
1. Shear stress induced alignment of actin fibers in endothelial cells along the direction of fluid flow compared to static condition, which confirmed that an in vitro shear stress model was successfully established.
2. Compared to static group, total LC3expression under shear stress was significantly increased as measured by western blotting. LC3punctation significantly increased as measured by immune fluorescence staining. pH value reduced in endothelial cells in shear group compared to static group as shown by acridine orange staining.3. Compared to static flow, DCFH-DA fluorescence increased significantly under shear status. It is confirmed that shear maintained endothelial autophagy related genes at the transcriptional level by PCR, and the effect can be reversed by pretreatment of EUK-134.
4. In human capillary endothelial cells transfected with pEGFP-LC3plasmid, it was revealed that shear group also maintained LC3punctate aggregation as measured by fluorescence microscope, which can be reversed with EUK-134pretreatment. It was found that4-hr H2O2treatment in HUVECs, increased significantly LC3fluorescence punctation intracellular aggregation.
5. It was also found that LC3expression reduced48h after carotid artery ligation. The number of autophagosome in endothelial cell cytoplasm reduced after carotid artery ligation.
Conclusions:
Shear stress maintains autophagy process in endothelial cells, which is in a cellular redox-dependent manner.
Part II SIRTl is involved in shear stress-induced autophagy
Ohjective:
To investigate if H2O2can mimic shear stress-regulated endothelial cell autophagy; to confirm if SIRT1is involved in shear-autophagy signaling pathway; to study the mechanism of SIRT1regulation of endothelial cell autophagy.
Methods:
1. The detection of SIRT1and autophagy related genes and proteins expression. SIRTl, ATG5, Bed in-1, MAP LC3expression was measured by PCR;LC3, mTOR, p-mTOR, ULK, p-ULK expression was measured by western blot in cells with or without SIRT1inhibitor Ex-527prctreatment before H2O2. LC3expression and its punctation aggregation were measured in Sirtl的siRNA transfected HUVECs and human capillary endothelial cells, respectively. LC3punctation was measured directly in pEGFP-LC3ovcrexpressing human microvascular endothelial cell line, which were pretreated with shear stress and/or Ex-527. Total LC3protein or LC3H/LC31was detected by western blot in pc I)NA3Flag-SIRT1transfected or resveratrol-treated cells
2. Sirtl-Foxola signaling detection:Sirtl and Foxola binding or Foxola aeetylation level were detected in Foxola-transfected HUVECs which were treated with H1O2and resveratrol. The effect of resveratrol treatment after pc DNA3Flag-Foxol a-AAA and wild type Foxo1a transfection on autophagy related gene expression was detected by PCR as well as the effect of co-transfected with the FOXO1A siRNA (Si-FOXO1A) and Flag-SIRT1.
3. Foxola nuclear location was observed in Flag-SIRT1, resveratrol treated HUVECs by immunofluorescence; Foxo1a target genes, and autophagy related gene expression was detected by PCR.
Results:
1. SIRT1-7were expressed in endothelial cells as revealed by gel electrophoresis of PCR products.
2. Shear stress induced SIRT1expression in endothelial cells.
3. There were no obvious changes of mTOR, p-mTOR, ULK, p-ULK in H2O2treated HUVECs.
4. ROS increased SIRT1gene expression. Both SIRT1gene and protein expression was increased in HUVECs after H2O2treatment in a time-dependent manner.
5. Resveratrol, an agonist of Sirt1, can enhance autophagy.
6. Resveratrol treatment increased ATG5, Beclin-1, and MAP_LC3mRNA expression in constitutively active Foxo1a transfected cells.
7. In Flag-FKHR transfected HUVECs, H2O2and resveratrol increased Foxo1a deacetylation level.
8. Flag-SIRT1overexpression increased the transeriptional level of autophagy related genes.
9. Sirtl inhibitor Ex-527inhibited autophagy:Increased ATG5, Beclin-1, and MAP_LC3mRNA levels induced by H2O2were reversed with Ex-527pretreatment. LC3punctatation decreased in pEGFP-LC3transfected human capillary vascular endothelial cells which underwent Ex-527pretreatment, in shear flow group.
10. Sirt1knock down also inhibited autophagy. LC3punctation aggregation was reduced in human capillary endothelial cells by Sirt1knocking down.
11. Both Ex-527and3-MA pretreatment in HUVECs reduced endothelial cells survival after oxidative stress challenge.
12. Sirt1effects on Foxola localization in HUVECs. SIRT1overexpression transfection and resveratrol treatment triggered nuclear localization of Foxola. SIRT1overexpression increased autophagy related gene transcription levels.
13. FOXO1A over expression in endothelial cells affects autophagy:MAP_LC3 significantly increased after overexpression of wild type or constitutively active Foxola.
14. FOXO1A knock down reversed A TG5. Bed in-1, and MAP LC3mRNA upregulation induced by SIRT1overexpression in HUVECs.
Conclusion:
Sirtl mediates shear-induced autophagy in endothelial cells. Sirtl regulates autophagy by Foxola deacetylation in endothelial cells.
Part Ⅲ Systemic biology study on the role of Sirt2in endothelial cells under oxidative stress
Objective:
To investigate the role of endothelial NAD+-dependcnt deacetylase Sirt2in endothelial cells under oxidative stress.
Methods:
Global gene expression changes were examined using cDNAmicroarray and PCR after Sirt2knocking down in primary HUVECs under oxidative stress. MTS assay was used to measure endothelial cell activity.
Results:
1. H2O2treatment induced oxidative stress response.
2. SIRT2expression was increased under oxidative stress.
3. Sirt2knocking down changed expression of340genes, which are mainly involved in cellular processes including actin binding, cellular amino acid metabolic process, transmembranc receptor protein scrine/threoninc kinase signaling, ferrous iron transport, protein transport and localization, cell morphogenesis, and functions associated with endosome membrane and the trans-Golgi network.
4. These above genes and associated functions were largely non-overlapping with those regulated by Sirtl knocking down.
5. Pharmacological inhibition of Sirt2attenuated oxidant-induced cell toxicity in endothelial cells.
Conclusions:Sirt2is functionally important in endothelial cells under oxidative stress, and it may have a primarily distinct role from Sirtl.
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