载脂蛋白嵌合模拟肽对巨噬细胞脂代谢和炎症反应的调控及机制探讨
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摘要
背景
巨噬细胞是动脉粥样硬化(AS)发生发展中最主要的细胞类型,与脂质沉积及炎症密切相关。循环中单核细胞募集至内皮下是动脉粥样硬化发生的最早期事件。单核细胞分化为巨噬细胞,吞噬大量含载脂蛋白B(apoB)且富含胆固醇的脂蛋白颗粒。在动脉粥样硬化的早期阶段,大部分被吞噬的胆固醇以胆固醇-脂肪酸酯的形式储存,导致了巨噬细胞源性泡沫细胞的形成。当动脉粥样硬化病变进一步进展,出现胆固醇酯含量的逐步下降,以及相应的非酯化的游离胆固醇(free cholesterol, FC)含量的进行性增加。FC在细胞的大量蓄积,导致巨噬细胞凋亡和继发性坏死,继而引起病变坏死、斑块破裂、血栓形成,最终导致临床急性心血管事件发生。同时越来越多研究者发现,在FC诱导凋亡发生前所触发的炎症反应是影响斑块稳定性、造成动脉粥样硬化病变进展的另一重要因素。
AS所致缺血性心脏疾病是中、老年人群发病和死亡的常见原因,探索能有效防治AS的措施一直是心血管疾病领域的研究热点。AS是一种多因素疾病,体内多种因子均不同作用地参与其发生发展,其中,载脂蛋白A-I(apoA-I)和载脂蛋白E(apoE)被认为是该疾病的两个保护性因子,二者均能通过多种途径拮抗AS,且相互存在协同效应。通过重组apoA-I和apoE全蛋白质(holoprotein)虽然能够治疗AS,但因二者均为大分子蛋白(分子量分别为28kD和34kD),故只能通过静脉给药,且制备不易、成本高昂,限制了其临床应用。因此,通过研制分子量更小而功能上相当的apoA-I模拟肽和apoE模拟肽用以治疗AS及其相关性疾病,被认为是防治AS方面很有前景的新策略,且已取得了较大进展。然而,现有apoA-I模拟肽和apoE模拟肽在抗AS方面均存在各自的不足,这在一定程度上降低了二者的治疗效应。于是有研究者利用天然apoA-I与apoE功能上的互补性,将apoE受体结合域与含有两性螺旋结构的apoA-I模拟肽共价结合,形成一种新型的具有双结构域的载脂蛋白嵌合模拟肽即Ac-hE-18A-NH2。研究发现这种双结构域的嵌合模拟肽可以促进成纤维细胞、HepG2细胞对低密度脂蛋白(LDL)的摄取、吸收和降解。进一步研究发现Ac-hE-18A-NH2模拟肽在体内具有抗炎及抗氧化的特性。在apoE基因敲除小鼠模型,静脉注射该模拟肽,血浆胆固醇水平明显下降。高胆固醇血症兔静脉注射Ac-hE-18A-NH2后,不仅显著降低了血浆胆固醇水平,而且通过降低血浆中过氧化氢脂质、增加高密度脂蛋白(HDL)对氧磷酶浓度、诱导超氧阴离子形成从而对抗氧化应激、改善内皮功能,从而起到抗动脉粥样硬化作用。
目的
观察载脂蛋白嵌合模拟肽Ac-hE-18A-NH2对氧化低密度脂蛋白(oxLDL)刺激下RAW 264.7巨噬细胞胆固醇流出、凋亡及炎症介质释放的影响,并探讨其可能的作用机制。
方法
RAW264.7巨噬细胞传代后接种于细胞培养板,分为三组：(1)胆固醇流出检测组：细胞种植于24孔板,用0.5μCi／孔3H-胆固醇和含50μg/ml oxLDL共同孵育24小时之后,给予不同浓度的Ac-hE-18A-NH2 (0-100μg/ml)干预24h,收集细胞用液体闪烁计数法检测胆固醇流出。采用酶联免疫吸附试验(ELISA)测定细胞内环磷酸腺苷(cAMP)含量,采用实时荧光定量PCR及Western blot检测三磷酸腺苷结合盒转运体A1(ABCA1),肝X受体α(LXRα)、过氧化物酶体增殖物激活受体γ(PPARγ)的mRNA及蛋白表达；(2)凋亡检测组：细胞种植于6孔板,50μg/ml oxLDL处理RAW264.7细胞48小时后加入不同浓度的模拟肽Ac-hE-18A-NH2(1、10、50、100μg/ml)和胆固醇流出促进剂β-环糊精(β-CD)或胆固醇流出阻断剂布雷菲得菌素(BFA)共同孵育24小时。Annexin V-FITC/PI细胞凋亡检测试剂盒及流式细胞仪检测细胞凋亡；分别通过试剂盒检测caspase-3活性及细胞内胆固醇含量；Western-blot检测细胞bcl-2蛋白的表达；(3)炎症反应组：oxLDL刺激RAW264.7巨噬细胞,给予不同浓度的模拟肽Ac-hE-18A-NH2(1-100μg／ml)干预,收集细胞,测定TNF-α分泌和mRNA表达水平。Western-blot检测ABCA1及P-IκB蛋白浓度。EMSA检测核因子-κB (NF-κB)活性。
结果
1.模拟肽Ac-hE-18A-NH2以浓度依赖及时间依赖方式促进巨噬细胞内胆固醇流出。1、10、50、100μg/ml Ac-hE-18A-NH2干预24小时后,其介导的胆固醇流出率分别为12.04±1.65%、16.19±1.45%、26.93±4.37%和24.58±2.43%；50μg/ml Ac-hE-18A-NH2干预细胞不同时间,其介导的胆固醇流出率分别为10.86±1.46%(6h),13.43±1.55%(12h),20.58±1.34%(18h),和26.93±4.37%(24h)。
2.Ac-hE-18A-NH2以浓度依赖方式增加细胞内cAMP水平,上调ABCA1、LXRα和PPARγmRNA和蛋白表达。
3.加用cAMP刺激剂8-Br-cAMP, Ac-hE-18A-NH2介导的胆固醇流出率明显增加(26.93±4.37,35.81±2.73；P<0.05),ABCA1mRNA表达增加了66.67%。而加用PPARγ特异性抑制剂预处理细胞后,PPARγ的表达几乎完全抑制,ABCA1和LXRα的表达也受到一定程度抑制,Ac-hE-18A-NH2介导的胆固醇流出率明显减少(26.93±4.37,17.23±1.93；P<0.01)。
4.OxLDL诱导的RAW264.7巨噬细胞的凋亡率随着oxLDL浓度的增加和处理时间的延长而显著提高。
5.50μg/ml oxLDL处理细胞48小时后,加入不同浓度的模拟肽Ac-hE-18A-NH2 (1、10、50、100μg/ml)干预,细胞凋亡率以浓度依赖的方式逐渐减少。
6.模拟肽Ac-hE-18A-NH2呈浓度依赖性的促进细胞内胆固醇流出和降低细胞内的胆固醇含量,降低caspase-3的活性,上调bcl-2的蛋白表达。
7.β-CD与Ac-hE-18A-NH2共同作用后胆固醇流出明显增加,细胞凋亡率相应减少。而通过BFA部分阻断介导的胆固醇流出,细胞凋亡率明显增加。
8.OxLDL刺激使RAW264.7巨噬细胞TNF-α分泌和mRNA表达明显增强,细胞内胆固醇蓄积,促进IκB磷酸化,并激活NF-κB。
9.Ac-hE-18A-NH2浓度依赖性降低TNF-α分泌及mRNA表达,上调ABCA1 mRNA和蛋白的表达,减少细胞内胆固醇含量,抑制NF-κB活化,并抑制IκB磷酸化。相同的实验条件下及作用浓度,D-4F对于TNF-α分泌的抑制作用不如Ac-hE-18A-NH2。
10.与oxLDL刺激组比较,50μg/ml Ac-hE-18A-NH2使上清TNF-α浓度降低56%,其mRNA表达降低67%,细胞内胆固醇含量降低65%,ABCA1 mRNA和蛋白表达均明显上调,NF-κB活性减少65.34%,胞浆中IκB-α蛋白水平明显升高,而p-IκB-α蛋白水平明显降低。
结论
1.模拟肽Ac-hE-18A-NH2可以明显促进巨噬细胞胆固醇流出,其机制可能与cAMP-ABCA1和PPARγ-LXRα-ABCA1两种途径有关。
2.模拟肽Ac-hE-18A-NH2可以明显抑制oxLDL诱导的巨噬细胞胆固醇凋亡,其作用与促进细胞胆固醇流出、减少细胞内胆固醇蓄积有关。
3.Ac-hE-18A-NH2能抑制oxLDL诱导的RAW264.7巨噬细胞TNF-α分泌和mRNA表达,FC-IκB/NF-KB-TNFα信号通路是其中作用途径之一。
Background
Macrophages are the most prominent cell type in atherosclerotic lesions and are associated with two hallmarks of the disease, lipid deposition and inflammation. Recruitment of circulating monocytes to the subendothelial space is one of the earliest events in atherogenesis. Monocytes differentiate into macrophages, which subsequently internalize large amount of atherogenic, cholesterol-rich lipoprotein particles. In the early stages of atherosclerosis, most of the internalized cholesterol is stored as cholesteryl esters, resulting in "foam cell" formation. As a lesion becomes more advanced, however, there is a progressive decrease in the cholesteryl ester content and a reciprocal increase in the unesterified, or "free" cholesterol (FC) content. FC accumulation is a potent inducer of macrophage apoptosis and secondary necrosis, which is thought to contribute to necrosis and plaque disruption, leading to acute atherothrombotic cardiovascular events. Another key characteristic of advanced, or "vulnerable," atherosclerotic lesion is the presence of a variety of inflammatory cytokines, many of which are thought to be secreted by macrophages and triggered by FC accumulation.
Atherosclerotic diseases are the leading cause of death in developed countries and part of developing countries. These facts highlight the need for effective therapies to manage atherosclerosis and thrombosis. In this regard, high-density lipoprotein (HDL)-based therapies have recently become the focus of attention. Apolipoprotein A-I (apoA-I) and apolipoprotein (apoE) are the main protein in HDL and exert diverse atheroprotective functions. However, both apoE and apoA-I are macromolecular protein (molecular weight of 28kD and 34kD, respectively) and can only be administered intravenously. In addition, difficult preparation and expensive cost limit their clinical application.Thus, their mimetic peptides which mimic the function of apolipoprotein with smaller molecular weight are increasingly considered as potential antiatherogenic strategy. Recently, a dual-domain peptide has been designed that possesses the arginine-rich domain (LRKLRKRLLR, 141-to 150-residue region of apo E) from apoE, covalently linked to the well-characterized class A amphipathic helical peptide 18A, high-affinity lipid-associating peptide (DWLKAFYDKVAEKL KEAF). The resulting peptide (Ac-hE-18A-NH2) has been shown to promote the rapid uptake and clearance of atherogenic apoB-containing lipoproteins in vitro and in dyslipidemic mouse models. In the Watanabe heritable hyperlipidemic (WHHL) rabbit, a single administration of the peptide Ac-hE18A-NH2 not only reduced plasma cholesterol levels but also restored endothelial function.
Objective
The aim of this study was to evaluate the effect of a dual-domain mimetic peptide, Ac-hE-18A-NH2 on the cholesterol efflux, apoptosis and inflammation response in RAW264.7 macrophages treated with oxidized low density lipoprotein(oxLDL), and to elucidate the possible mechanisms.
Methods
RAW264.7 macrophages were divided into three groups:(1) Cholesterol efflux group:RAW264.7 macrophages were incubated in the medium containing various concentration of the peptide, Ac-hE-18A-NH2 (1,10,50 and 100μg/ml) for 24 hours. The intracellular cAMP level was determined by ELISA. ABCA1、LXRαand PPARγexpression in macrophages was quantitated by realtime RT-PCR and Western blot analysis. (2) Apoptosis group:The cells were exposed to 50μg/ml oxLDL for 48 hrs, and then the cells were incubated with the peptide Ac-hE-18A-NH2 with various concentrations. The apoptosis was detected using Annexin V-FITC staining and flow cytometric analysis. The caspase-3 activity and intracellular cholesterol content were measured using commercially available quantitation kits. Bcl-2 protein expression in macrophages was detected by Western blot analysis. In some experiments, the cells were co-treated withβ-cyclodextrin (a cholesterol efflux stimulator) or BFA (a cholesterol efflux blocker) for 24hours. (3) Inflammation group:Macrophages were incubated in the medium containing various concentrations of Ac-hE18A-NH2 (1-50μg/ml) with ox-LDL (50μg/ml) stimulated. The TNF-a level and intracellular cholesterol content were measured using commercially available quantitation kits. TNFαand ABCA1 mRNA expression were detected by Real-time PCR. ABCA1 and IκB protein expression in macrophages was determined by Western blot analysis. NF-κB activity was evaluated by Electrophoretic Mobility Shift Assay (EMSA).
Results
1. The peptide Ac-hE-18A-NH2 significantly increased the cholesterol efflux in concentration-and time-dependent manner. Compared with the control group,1.3-fold increase in 10μg/ml peptide Ac-hE-18A-NH2-mediated cholesterol efflux was seen, whereas 0.7-fold increase was observed in 1μg/ml Ac-hE-18A-NH2-mediated cholesterol efflux. The maximum cholesterol efflux mediated by the peptide was occurred at 50μg/ml (26.93±4.37%). Cholesterol efflux from macrophages at different time points was 10.86±1.46%(6 hrs),13.43±1.55%(12 hrs), 20.58±1.34%(18 hrs), and 26.93±4.37%(24 hrs), respectively.
2. Concomitantly, Ac-hE-18A-NH2 increased intracellular cAMP level, ABCA1 mRNA and protein expression in dose-dependent manner, consistent with the changes of cholesterol efflux from macrophages.
3.8-Br-cAMP was a potent activator of cholesterol efflux and ABCA1 expression during the process of cholesterol efflux mediated by Ac-hE-18A-NH2. Moreover, Ac-hE-18A-NH2 upregulated the expression of LXRa and PPARy. Addition of GW9662 markedly inhibited the increase of ABCA1 gene expression and Ac-hE-18A-NH2-mediated cholesterol efflux.
4. After treated with 50μg/ml ox-LDL for various time points, the apoptotic rate of RAW264.7 macrophages increased in a time-dependent manner. Ox-LDL with increasing concentration induced macrophages apoptosis in a dose-dependent manner.
5. The peptide Ac-hE-18A-NH2 with various concentrations (1μg/wl,10μg/ml, and 50μg/ml) inhibited the ox-LDL-mediated apoptosis in a concentration-dependent manner.
6. The peptide also decreased the caspase-3 activity and increased bcl-2 expression in macrophages in a dose-dependent manner. It was accompanied by an increased rate of intracellular cholesterol efflux, and decreased total cholesterol levels in cells in a concentration-dependent manner.
7. Moreover, blockage of cholesterol efflux by brefeldin A decreased the protective effect of Ac-hE-18A-NH2 on ox-LDL induced apoptosis While increase of the cholesterol efflux byβ-cyclodextrin led to a dramatic decrease in the apoptotic rate of cells.
8. OxLDL stimulation induced a significant increase of TNFa secretion, mRNA expression, cholesterol accumulation and NF-κB activity in RAW264.7 macrophages.9. Ac-hE-18A-NH2 reduced TNFa secretion and mRNA expression, up-regulated the ABCA1 mRNA and protein expression, reduced the intracellular cholesterol content and inhibited NF-κB activation in a dose-dependent manner.
10. Treatment with Ac-hE-18A-NH2 at 50μg/ml significantly suppressed TNFa secretion by 56%, reduced intracellular cholesterol content by 65%, inhibited NF-κB activation by 65.34%, upregulated ABCA1 mRNA and protein expression, and suppressed IκB-αphosphorylation as compared with ox-LDL stimulated group. Under the same condition and the same concentration, Ac-hE-18A-NH2 is more efficient than D-4F (apoA-I mimetic peptide) to inhibit the inflammatory response induced by ox-LDL in macrophages.
Conclusions
1. Ac-hE-18A-NH2 affects cholesterol efflux, cAMP level and ABCA1 expression of macrophages, and the cAMP is probably involved. Furthermore, the pathway of LXRα-PPARγ-ABCA1 may also be involved in this process.
2. The mimetic peptide Ac-hE-18A-NH2 exerts a protective effect against macrophage apoptosis, through reducing the accumulation of cholesterol.
3. Ac-hE-18A-NH2 could suppress TNFa secretion and mRNA expression in ox-LDL-stimulated RAW264.7 macrophages by IKBa-NF-KB signaling pathway.
巨噬细胞是动脉粥样硬化(AS)发生发展中最主要的细胞类型,与脂质沉积及炎症密切相关。循环中单核细胞募集至内皮下是动脉粥样硬化发生的最早期事件。单核细胞分化为巨噬细胞,吞噬大量含载脂蛋白B(apoB)且富含胆固醇的脂蛋白颗粒。在动脉粥样硬化的早期阶段,大部分被吞噬的胆固醇以胆固醇-脂肪酸酯的形式储存,导致了巨噬细胞源性泡沫细胞的形成。当动脉粥样硬化病变进一步进展,出现胆固醇酯含量的逐步下降,以及相应的非酯化的游离胆固醇(free cholesterol, FC)含量的进行性增加。FC在细胞的大量蓄积,导致巨噬细胞凋亡和继发性坏死,继而引起病变坏死、斑块破裂、血栓形成,最终导致临床急性心血管事件发生。同时越来越多研究者发现,在FC诱导凋亡发生前所触发的炎症反应是影响斑块稳定性、造成动脉粥样硬化病变进展的另一重要因素。
AS所致缺血性心脏疾病是中、老年人群发病和死亡的常见原因,探索能有效防治AS的措施一直是心血管疾病领域的研究热点。AS是一种多因素疾病,体内多种因子均不同作用地参与其发生发展,其中,载脂蛋白A-I(apoA-I)和载脂蛋白E(apoE)被认为是该疾病的两个保护性因子,二者均能通过多种途径拮抗AS,且相互存在协同效应。通过重组apoA-I和apoE全蛋白质(holoprotein)虽然能够治疗AS,但因二者均为大分子蛋白(分子量分别为28kD和34kD),故只能通过静脉给药,且制备不易、成本高昂,限制了其临床应用。因此,通过研制分子量更小而功能上相当的apoA-I模拟肽和apoE模拟肽用以治疗AS及其相关性疾病,被认为是防治AS方面很有前景的新策略,且已取得了较大进展。然而,现有apoA-I模拟肽和apoE模拟肽在抗AS方面均存在各自的不足,这在一定程度上降低了二者的治疗效应。于是有研究者利用天然apoA-I与apoE功能上的互补性,将apoE受体结合域与含有两性螺旋结构的apoA-I模拟肽共价结合,形成一种新型的具有双结构域的载脂蛋白嵌合模拟肽即Ac-hE-18A-NH2。研究发现这种双结构域的嵌合模拟肽可以促进成纤维细胞、HepG2细胞对低密度脂蛋白(LDL)的摄取、吸收和降解。进一步研究发现Ac-hE-18A-NH2模拟肽在体内具有抗炎及抗氧化的特性。在apoE基因敲除小鼠模型,静脉注射该模拟肽,血浆胆固醇水平明显下降。高胆固醇血症兔静脉注射Ac-hE-18A-NH2后,不仅显著降低了血浆胆固醇水平,而且通过降低血浆中过氧化氢脂质、增加高密度脂蛋白(HDL)对氧磷酶浓度、诱导超氧阴离子形成从而对抗氧化应激、改善内皮功能,从而起到抗动脉粥样硬化作用。
目的
观察载脂蛋白嵌合模拟肽Ac-hE-18A-NH2对氧化低密度脂蛋白(oxLDL)刺激下RAW 264.7巨噬细胞胆固醇流出、凋亡及炎症介质释放的影响,并探讨其可能的作用机制。
方法
RAW264.7巨噬细胞传代后接种于细胞培养板,分为三组：(1)胆固醇流出检测组：细胞种植于24孔板,用0.5μCi／孔3H-胆固醇和含50μg/ml oxLDL共同孵育24小时之后,给予不同浓度的Ac-hE-18A-NH2 (0-100μg/ml)干预24h,收集细胞用液体闪烁计数法检测胆固醇流出。采用酶联免疫吸附试验(ELISA)测定细胞内环磷酸腺苷(cAMP)含量,采用实时荧光定量PCR及Western blot检测三磷酸腺苷结合盒转运体A1(ABCA1),肝X受体α(LXRα)、过氧化物酶体增殖物激活受体γ(PPARγ)的mRNA及蛋白表达；(2)凋亡检测组：细胞种植于6孔板,50μg/ml oxLDL处理RAW264.7细胞48小时后加入不同浓度的模拟肽Ac-hE-18A-NH2(1、10、50、100μg/ml)和胆固醇流出促进剂β-环糊精(β-CD)或胆固醇流出阻断剂布雷菲得菌素(BFA)共同孵育24小时。Annexin V-FITC/PI细胞凋亡检测试剂盒及流式细胞仪检测细胞凋亡；分别通过试剂盒检测caspase-3活性及细胞内胆固醇含量；Western-blot检测细胞bcl-2蛋白的表达；(3)炎症反应组：oxLDL刺激RAW264.7巨噬细胞,给予不同浓度的模拟肽Ac-hE-18A-NH2(1-100μg／ml)干预,收集细胞,测定TNF-α分泌和mRNA表达水平。Western-blot检测ABCA1及P-IκB蛋白浓度。EMSA检测核因子-κB (NF-κB)活性。
结果
1.模拟肽Ac-hE-18A-NH2以浓度依赖及时间依赖方式促进巨噬细胞内胆固醇流出。1、10、50、100μg/ml Ac-hE-18A-NH2干预24小时后,其介导的胆固醇流出率分别为12.04±1.65%、16.19±1.45%、26.93±4.37%和24.58±2.43%；50μg/ml Ac-hE-18A-NH2干预细胞不同时间,其介导的胆固醇流出率分别为10.86±1.46%(6h),13.43±1.55%(12h),20.58±1.34%(18h),和26.93±4.37%(24h)。
2.Ac-hE-18A-NH2以浓度依赖方式增加细胞内cAMP水平,上调ABCA1、LXRα和PPARγmRNA和蛋白表达。
3.加用cAMP刺激剂8-Br-cAMP, Ac-hE-18A-NH2介导的胆固醇流出率明显增加(26.93±4.37,35.81±2.73；P<0.05),ABCA1mRNA表达增加了66.67%。而加用PPARγ特异性抑制剂预处理细胞后,PPARγ的表达几乎完全抑制,ABCA1和LXRα的表达也受到一定程度抑制,Ac-hE-18A-NH2介导的胆固醇流出率明显减少(26.93±4.37,17.23±1.93；P<0.01)。
4.OxLDL诱导的RAW264.7巨噬细胞的凋亡率随着oxLDL浓度的增加和处理时间的延长而显著提高。
5.50μg/ml oxLDL处理细胞48小时后,加入不同浓度的模拟肽Ac-hE-18A-NH2 (1、10、50、100μg/ml)干预,细胞凋亡率以浓度依赖的方式逐渐减少。
6.模拟肽Ac-hE-18A-NH2呈浓度依赖性的促进细胞内胆固醇流出和降低细胞内的胆固醇含量,降低caspase-3的活性,上调bcl-2的蛋白表达。
7.β-CD与Ac-hE-18A-NH2共同作用后胆固醇流出明显增加,细胞凋亡率相应减少。而通过BFA部分阻断介导的胆固醇流出,细胞凋亡率明显增加。
8.OxLDL刺激使RAW264.7巨噬细胞TNF-α分泌和mRNA表达明显增强,细胞内胆固醇蓄积,促进IκB磷酸化,并激活NF-κB。
9.Ac-hE-18A-NH2浓度依赖性降低TNF-α分泌及mRNA表达,上调ABCA1 mRNA和蛋白的表达,减少细胞内胆固醇含量,抑制NF-κB活化,并抑制IκB磷酸化。相同的实验条件下及作用浓度,D-4F对于TNF-α分泌的抑制作用不如Ac-hE-18A-NH2。
10.与oxLDL刺激组比较,50μg/ml Ac-hE-18A-NH2使上清TNF-α浓度降低56%,其mRNA表达降低67%,细胞内胆固醇含量降低65%,ABCA1 mRNA和蛋白表达均明显上调,NF-κB活性减少65.34%,胞浆中IκB-α蛋白水平明显升高,而p-IκB-α蛋白水平明显降低。
结论
1.模拟肽Ac-hE-18A-NH2可以明显促进巨噬细胞胆固醇流出,其机制可能与cAMP-ABCA1和PPARγ-LXRα-ABCA1两种途径有关。
2.模拟肽Ac-hE-18A-NH2可以明显抑制oxLDL诱导的巨噬细胞胆固醇凋亡,其作用与促进细胞胆固醇流出、减少细胞内胆固醇蓄积有关。
3.Ac-hE-18A-NH2能抑制oxLDL诱导的RAW264.7巨噬细胞TNF-α分泌和mRNA表达,FC-IκB/NF-KB-TNFα信号通路是其中作用途径之一。
Background
Macrophages are the most prominent cell type in atherosclerotic lesions and are associated with two hallmarks of the disease, lipid deposition and inflammation. Recruitment of circulating monocytes to the subendothelial space is one of the earliest events in atherogenesis. Monocytes differentiate into macrophages, which subsequently internalize large amount of atherogenic, cholesterol-rich lipoprotein particles. In the early stages of atherosclerosis, most of the internalized cholesterol is stored as cholesteryl esters, resulting in "foam cell" formation. As a lesion becomes more advanced, however, there is a progressive decrease in the cholesteryl ester content and a reciprocal increase in the unesterified, or "free" cholesterol (FC) content. FC accumulation is a potent inducer of macrophage apoptosis and secondary necrosis, which is thought to contribute to necrosis and plaque disruption, leading to acute atherothrombotic cardiovascular events. Another key characteristic of advanced, or "vulnerable," atherosclerotic lesion is the presence of a variety of inflammatory cytokines, many of which are thought to be secreted by macrophages and triggered by FC accumulation.
Atherosclerotic diseases are the leading cause of death in developed countries and part of developing countries. These facts highlight the need for effective therapies to manage atherosclerosis and thrombosis. In this regard, high-density lipoprotein (HDL)-based therapies have recently become the focus of attention. Apolipoprotein A-I (apoA-I) and apolipoprotein (apoE) are the main protein in HDL and exert diverse atheroprotective functions. However, both apoE and apoA-I are macromolecular protein (molecular weight of 28kD and 34kD, respectively) and can only be administered intravenously. In addition, difficult preparation and expensive cost limit their clinical application.Thus, their mimetic peptides which mimic the function of apolipoprotein with smaller molecular weight are increasingly considered as potential antiatherogenic strategy. Recently, a dual-domain peptide has been designed that possesses the arginine-rich domain (LRKLRKRLLR, 141-to 150-residue region of apo E) from apoE, covalently linked to the well-characterized class A amphipathic helical peptide 18A, high-affinity lipid-associating peptide (DWLKAFYDKVAEKL KEAF). The resulting peptide (Ac-hE-18A-NH2) has been shown to promote the rapid uptake and clearance of atherogenic apoB-containing lipoproteins in vitro and in dyslipidemic mouse models. In the Watanabe heritable hyperlipidemic (WHHL) rabbit, a single administration of the peptide Ac-hE18A-NH2 not only reduced plasma cholesterol levels but also restored endothelial function.
Objective
The aim of this study was to evaluate the effect of a dual-domain mimetic peptide, Ac-hE-18A-NH2 on the cholesterol efflux, apoptosis and inflammation response in RAW264.7 macrophages treated with oxidized low density lipoprotein(oxLDL), and to elucidate the possible mechanisms.
Methods
RAW264.7 macrophages were divided into three groups:(1) Cholesterol efflux group:RAW264.7 macrophages were incubated in the medium containing various concentration of the peptide, Ac-hE-18A-NH2 (1,10,50 and 100μg/ml) for 24 hours. The intracellular cAMP level was determined by ELISA. ABCA1、LXRαand PPARγexpression in macrophages was quantitated by realtime RT-PCR and Western blot analysis. (2) Apoptosis group:The cells were exposed to 50μg/ml oxLDL for 48 hrs, and then the cells were incubated with the peptide Ac-hE-18A-NH2 with various concentrations. The apoptosis was detected using Annexin V-FITC staining and flow cytometric analysis. The caspase-3 activity and intracellular cholesterol content were measured using commercially available quantitation kits. Bcl-2 protein expression in macrophages was detected by Western blot analysis. In some experiments, the cells were co-treated withβ-cyclodextrin (a cholesterol efflux stimulator) or BFA (a cholesterol efflux blocker) for 24hours. (3) Inflammation group:Macrophages were incubated in the medium containing various concentrations of Ac-hE18A-NH2 (1-50μg/ml) with ox-LDL (50μg/ml) stimulated. The TNF-a level and intracellular cholesterol content were measured using commercially available quantitation kits. TNFαand ABCA1 mRNA expression were detected by Real-time PCR. ABCA1 and IκB protein expression in macrophages was determined by Western blot analysis. NF-κB activity was evaluated by Electrophoretic Mobility Shift Assay (EMSA).
Results
1. The peptide Ac-hE-18A-NH2 significantly increased the cholesterol efflux in concentration-and time-dependent manner. Compared with the control group,1.3-fold increase in 10μg/ml peptide Ac-hE-18A-NH2-mediated cholesterol efflux was seen, whereas 0.7-fold increase was observed in 1μg/ml Ac-hE-18A-NH2-mediated cholesterol efflux. The maximum cholesterol efflux mediated by the peptide was occurred at 50μg/ml (26.93±4.37%). Cholesterol efflux from macrophages at different time points was 10.86±1.46%(6 hrs),13.43±1.55%(12 hrs), 20.58±1.34%(18 hrs), and 26.93±4.37%(24 hrs), respectively.
2. Concomitantly, Ac-hE-18A-NH2 increased intracellular cAMP level, ABCA1 mRNA and protein expression in dose-dependent manner, consistent with the changes of cholesterol efflux from macrophages.
3.8-Br-cAMP was a potent activator of cholesterol efflux and ABCA1 expression during the process of cholesterol efflux mediated by Ac-hE-18A-NH2. Moreover, Ac-hE-18A-NH2 upregulated the expression of LXRa and PPARy. Addition of GW9662 markedly inhibited the increase of ABCA1 gene expression and Ac-hE-18A-NH2-mediated cholesterol efflux.
4. After treated with 50μg/ml ox-LDL for various time points, the apoptotic rate of RAW264.7 macrophages increased in a time-dependent manner. Ox-LDL with increasing concentration induced macrophages apoptosis in a dose-dependent manner.
5. The peptide Ac-hE-18A-NH2 with various concentrations (1μg/wl,10μg/ml, and 50μg/ml) inhibited the ox-LDL-mediated apoptosis in a concentration-dependent manner.
6. The peptide also decreased the caspase-3 activity and increased bcl-2 expression in macrophages in a dose-dependent manner. It was accompanied by an increased rate of intracellular cholesterol efflux, and decreased total cholesterol levels in cells in a concentration-dependent manner.
7. Moreover, blockage of cholesterol efflux by brefeldin A decreased the protective effect of Ac-hE-18A-NH2 on ox-LDL induced apoptosis While increase of the cholesterol efflux byβ-cyclodextrin led to a dramatic decrease in the apoptotic rate of cells.
8. OxLDL stimulation induced a significant increase of TNFa secretion, mRNA expression, cholesterol accumulation and NF-κB activity in RAW264.7 macrophages.9. Ac-hE-18A-NH2 reduced TNFa secretion and mRNA expression, up-regulated the ABCA1 mRNA and protein expression, reduced the intracellular cholesterol content and inhibited NF-κB activation in a dose-dependent manner.
10. Treatment with Ac-hE-18A-NH2 at 50μg/ml significantly suppressed TNFa secretion by 56%, reduced intracellular cholesterol content by 65%, inhibited NF-κB activation by 65.34%, upregulated ABCA1 mRNA and protein expression, and suppressed IκB-αphosphorylation as compared with ox-LDL stimulated group. Under the same condition and the same concentration, Ac-hE-18A-NH2 is more efficient than D-4F (apoA-I mimetic peptide) to inhibit the inflammatory response induced by ox-LDL in macrophages.
Conclusions
1. Ac-hE-18A-NH2 affects cholesterol efflux, cAMP level and ABCA1 expression of macrophages, and the cAMP is probably involved. Furthermore, the pathway of LXRα-PPARγ-ABCA1 may also be involved in this process.
2. The mimetic peptide Ac-hE-18A-NH2 exerts a protective effect against macrophage apoptosis, through reducing the accumulation of cholesterol.
3. Ac-hE-18A-NH2 could suppress TNFa secretion and mRNA expression in ox-LDL-stimulated RAW264.7 macrophages by IKBa-NF-KB signaling pathway.
引文
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