NLRP3炎症小体及其下游炎症因子在动脉粥样硬化炎症反应中的作用
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摘要
背景：目前冠心病(CAD)已成为发达国家患者死亡的首要原因。以血管壁功能紊乱及斑块形成为特征的动脉粥样硬化是冠心病形成及发展的主要病理过程。内皮功能紊乱引起的自由基增加,低密度脂蛋白(LDL)、感染性微生物、剪切应力、毒素、高血压等因素的共同作用会诱导慢性炎症反应的发生最终导致动脉粥样硬化的形成。慢性炎症反应是动脉粥样硬化发生发展过程中的重要推动力，动脉壁的脂质沉积以及外周血炎性细胞的浸润被认为是动脉粥样硬化斑块形成及发展的主要标志。
近年来的研究提示先天免疫模式识别受体（pattern-recognition receptors, PRRs）介导的炎症反应在动脉粥样硬化的发生发展过程中发挥了重要作用。它们通过识别病原体相关分子模式（pathogen-associated molecular patterns，PAMPs)以及内源性危险信号（endogenous danger signals，DAMPs)使免疫细胞受到活化并分泌一系列的细胞因子从而促进动脉壁的炎症反应过程。NLRP3炎症小体是刚刚引起关注的一种细胞内模式识别受体，当配体与NLRP3结合后促进炎症小体的形成，并对caspase-1进行自身激活，最终导致IL-1β和IL-18的成熟及分泌。现有研究结果提示NLRP3炎症小体可能参与了动脉粥样硬化炎症反应的发生，但是部分研究结论仍然存在矛盾。因此，清楚认识NLRP3炎症小体及其下游炎症因子在动脉粥样硬化中的作用，对于认识细胞内模式识别受体在人动脉粥样硬化形成及发展中的作用具有重要意义。
方法：该实验主要分为两大部分：第一部分观察临床冠心病患者外周血单核细胞内NLRP3炎症小体及其下游炎症因子的表达情况。通过ELISA, real-timePCR和Western Blot等方法对20例健康对照以及64例不同程度冠心病（稳定性心绞痛，不稳定性心绞痛）患者外周血单核细胞NLRP3及其下游炎症因子的mRNA和蛋白表达水平进行检测；观察30例急性ST段抬高型心肌梗死患者NLRP3炎症小体及其下游炎症因子的动态表达，共选取4个时间点依次为：胸痛发作6小时以内,胸痛发作后48~72小时,心肌梗死发病后1周以及心肌梗死后4~6周，通过ELISA, real-time PCR的方法对急性ST段抬高型心肌梗死患者发病不同时间点的外周血单核细胞内NLRP3及其下游炎症因子的表达进行观察。第二部分，从细胞水平探讨NLRP3炎症小体的作用，采用ox-LDL、ox-HDL、HDL三种脂蛋白分别作用于人单核细胞系Thp-1之后，观察NLRP3及其下游炎症因子的表达变化；通过RNA干扰技术，构建NLRP3小干扰RNA下调NLRP3基因表达，再次给予ox-LDL、ox-HDL、HDL，观察下调NLRP3基因表达后对下游caspase-1、IL-1β和IL-18活化情况的影响；观察人脐静脉内皮细胞系ECV304中是否存在NLRP3及其下游炎症因子的表达，同样给予ox-LDL、ox-HDL、HDL作用后观察NLRP3及其下游炎症因子的表达变化。
结果：1.NLRP3及其下游炎症因子在冠心病患者中随冠心病的病情及冠状动脉粥样硬化的严重程度增加而表达逐渐增加；2.NLRP3及其下游炎症因子在急性ST段抬高型心肌梗死发病过程中的4个时间点：胸痛发作6小时以内(3.5±1.1小时)，胸痛发作后48~72小时(57.0±9.4小时)，心肌梗死发病后1周(7±1天)以及心肌梗死后4~6周(5.1±0.7周)具有动态变化；3.氧化低密度脂蛋白（ox-LDL），氧化高密度脂蛋白（ox-HDL）作用于单核细胞后可以促进NLRP3表达，并进一步活化NLRP3炎症小体下游的caspase-1，诱发IL-1β和IL-18的分泌，这种活化效应具有浓度依赖性；高密度脂蛋白（HDL）作用于单核细胞随作用浓度的升高NLRP3及其下游炎症因子的表达逐渐减弱；干预NLRP3炎症小体能够明显抑制细胞因子的产生；4.在人脐静脉内皮细胞系ECV304中存在NLRP3及其下游炎症因子的mRNA和蛋白水平的表达；给予氧化低密度脂蛋白（ox-LDL）和氧化高密度脂蛋白（ox-HDL）刺激后，能够促进NLRP3及其下游炎症因子的mRNA和蛋白水平的表达，促进炎症介质IL-1β和IL-18的释放。
结论：1. NLRP3及其下游炎症因子在冠心病患者中随冠心病的病情及冠状动脉粥样硬化的严重程度增加而表达逐渐增加，提示NLRP3及其下游炎症因子可能与冠心病的病情及动脉粥样硬化病变严重程度相关；2. NLRP3及其下游炎症因子在急性ST段抬高型心肌梗死发病过程中具有动态变化，提示NLRP3及其下游炎症因子可能参与了急性ST段抬高型心肌梗死发病过程中的急性炎症反应；3.在人单核细胞和内皮细胞中都存在NLRP3及其下游炎症因子的表达，在脂蛋白的作用下能够表现出不同程度的活化和抑制作用，干预NLRP3炎症小体能够明显抑制细胞因子的产生，提示NLRP3炎症小体在参与动脉粥样硬化发生发展的多种细胞内表达，诱导炎症介质的释放，能够全面参与动脉粥样硬化发生发展过程中的炎症反应，干预NLRP3有可能成为防治动脉粥样硬化新的靶点。
Background: Coronary artery disease (CAD) is the leading cause of mortality inmost developed countries. Atherosclerosis, which is a progressive disorder of the vesselwalls with the formation of plaques throughout the arterial system, is the essentialpathological process of CAD. It is general accepted that a complex endothelialdysfunction induced by free radicals, low density lipoproteins (LDL), infectiousmicroorganisms, shear stress, toxins, hypertension or a combination of these and otherfactors will lead to an chronic inflammatory response which leads to atherosclerosis.Chronic inflammation is recognized as a major driving force in atherogenesis. The sitesof atherosclerotic plaque development in the arterial wall are characterized bycholesterol accumulation and infiltration of peripheral blood monocytes, whichgradually differentiate into macrophages.
Pattern recognition receptor (PRR)-mediated signaling pathways have recentlybeen elucidated to bridge innate immune system and atherosclerosis, they can detectpathogen-associated molecular patterns (PAMPs) and endogenous danger signals(DAMPs). Once activated, the monocytes and macrophages secrete a myriad ofcytokines that promote inflammation in the arterial wall. NOD-like receptor family,pyrin domain containing3(NLRP3) is a member of the NLR family. Upon activation,NLRP3recruits the adapter protein and forms NLRP3inflammasome. The NLRP3inflammasome assembles in response to a variety of exogenous and endogenousactivators as an initial priming step，and thereby initiates IL-1β and I-18processing, akey step in the innate immune response. As the role of NLRP3inflamasome in humanatherosclerosis is unclear yet, confirm potential role of NLRP3inflamasome in thedevelopment of atherosclerosis will provide a new theoretical basis for the innateimmune system participating in atherosclerosis development and highlight the potentialof NLRP3inflammasome as a target for prevention and treatment of atherosclerosis.
Method: There are two parts in this study: the first part we observed theexpression of NLRP3and downstream cytokines in patients with CAD by ELISA,real-time PCR and Western Blot. Sixty-four CAD patients (patients with stable anginaand unstable angina) and twenty healthy controls were enrolled in this study. In addition,thirty patients with STEMI were recruited in this study. The expression levels ofNLRP3and downstream cytokines were determined at four different time points: within6hours after symptom onset (3.5±1.1h), acute phase at48~72hours (57.0±9.4h),convalescence stage at1week (7±1d) and stable period at4~6weeks (5.1±0.7w); thesecond part we study the role of NLRP3on the cell level, ox-LDL、HDL、ox-HDL wereused to stimulate human mononuclear cell line (Thp-1) and human umbilical veinendothelial cell line (ECV304), then expression of NLRP3and downstream cytokineswere observed. The following, we used NLRP3siRNA to down regulate the NLRP3mRNA expression, again gave ox-LDL、HDL and ox-HDL act on human mononuclearcell line Thp-1, observed the activation of NLRP3and downstream caspase-1、IL-1βandIL-18.
Results:1. These results showed that the expression of NLRP3and downstreamcytokines gradually increased along with the increasing severity of CAD;2. NLRP3anddownstream cytokines had a dynamic variation in patients with STEMI;3. ox-LDL、ox-HDL acted on mononuclear cells can promote the NLRP3expression, and furtheractivated the downstream caspase-1, inducd the secretion of IL-1β and IL-18; theactivation effect was concentration dependent, NLRP3and downstream cytokinesdecreased with the treatment of HDL;4.The mRNA and protein expression of NLRP3and downstream cytokines were existed in human umbilical vein endothelial cells(ECV304), ox-LDL and ox-HDL can promote the expression of NLRP3and release ofdownstream IL-1β and IL-18;5. Intervention with NLRP3inflammasome couldsignificantly inhibit the release of downstream IL-1β and IL-18.
Conclusion：1. the expression of NLRP3and downstream cytokines graduallyincreased along with the increasing severity of CAD, indicating that NLRP3anddownstream cytokines might be relevant with the severity of CAD；2. NLRP3anddownstream cytokines had a dynamic variation in STEMI, indicating that NLRP3anddownstream cytokines might be involved in the acute inflamatory response of STEMI；3.Lipoprotein acted on human mononuclear cells and endothelial cells can showdifferent degree of activation and inhibition, NLRP3expressed in a variety of cells,inducing the release of inflammatory mediators, fully participated in the occurrence and development of atherosclerosis.
近年来的研究提示先天免疫模式识别受体（pattern-recognition receptors, PRRs）介导的炎症反应在动脉粥样硬化的发生发展过程中发挥了重要作用。它们通过识别病原体相关分子模式（pathogen-associated molecular patterns，PAMPs)以及内源性危险信号（endogenous danger signals，DAMPs)使免疫细胞受到活化并分泌一系列的细胞因子从而促进动脉壁的炎症反应过程。NLRP3炎症小体是刚刚引起关注的一种细胞内模式识别受体，当配体与NLRP3结合后促进炎症小体的形成，并对caspase-1进行自身激活，最终导致IL-1β和IL-18的成熟及分泌。现有研究结果提示NLRP3炎症小体可能参与了动脉粥样硬化炎症反应的发生，但是部分研究结论仍然存在矛盾。因此，清楚认识NLRP3炎症小体及其下游炎症因子在动脉粥样硬化中的作用，对于认识细胞内模式识别受体在人动脉粥样硬化形成及发展中的作用具有重要意义。
方法：该实验主要分为两大部分：第一部分观察临床冠心病患者外周血单核细胞内NLRP3炎症小体及其下游炎症因子的表达情况。通过ELISA, real-timePCR和Western Blot等方法对20例健康对照以及64例不同程度冠心病（稳定性心绞痛，不稳定性心绞痛）患者外周血单核细胞NLRP3及其下游炎症因子的mRNA和蛋白表达水平进行检测；观察30例急性ST段抬高型心肌梗死患者NLRP3炎症小体及其下游炎症因子的动态表达，共选取4个时间点依次为：胸痛发作6小时以内,胸痛发作后48~72小时,心肌梗死发病后1周以及心肌梗死后4~6周，通过ELISA, real-time PCR的方法对急性ST段抬高型心肌梗死患者发病不同时间点的外周血单核细胞内NLRP3及其下游炎症因子的表达进行观察。第二部分，从细胞水平探讨NLRP3炎症小体的作用，采用ox-LDL、ox-HDL、HDL三种脂蛋白分别作用于人单核细胞系Thp-1之后，观察NLRP3及其下游炎症因子的表达变化；通过RNA干扰技术，构建NLRP3小干扰RNA下调NLRP3基因表达，再次给予ox-LDL、ox-HDL、HDL，观察下调NLRP3基因表达后对下游caspase-1、IL-1β和IL-18活化情况的影响；观察人脐静脉内皮细胞系ECV304中是否存在NLRP3及其下游炎症因子的表达，同样给予ox-LDL、ox-HDL、HDL作用后观察NLRP3及其下游炎症因子的表达变化。
结果：1.NLRP3及其下游炎症因子在冠心病患者中随冠心病的病情及冠状动脉粥样硬化的严重程度增加而表达逐渐增加；2.NLRP3及其下游炎症因子在急性ST段抬高型心肌梗死发病过程中的4个时间点：胸痛发作6小时以内(3.5±1.1小时)，胸痛发作后48~72小时(57.0±9.4小时)，心肌梗死发病后1周(7±1天)以及心肌梗死后4~6周(5.1±0.7周)具有动态变化；3.氧化低密度脂蛋白（ox-LDL），氧化高密度脂蛋白（ox-HDL）作用于单核细胞后可以促进NLRP3表达，并进一步活化NLRP3炎症小体下游的caspase-1，诱发IL-1β和IL-18的分泌，这种活化效应具有浓度依赖性；高密度脂蛋白（HDL）作用于单核细胞随作用浓度的升高NLRP3及其下游炎症因子的表达逐渐减弱；干预NLRP3炎症小体能够明显抑制细胞因子的产生；4.在人脐静脉内皮细胞系ECV304中存在NLRP3及其下游炎症因子的mRNA和蛋白水平的表达；给予氧化低密度脂蛋白（ox-LDL）和氧化高密度脂蛋白（ox-HDL）刺激后，能够促进NLRP3及其下游炎症因子的mRNA和蛋白水平的表达，促进炎症介质IL-1β和IL-18的释放。
结论：1. NLRP3及其下游炎症因子在冠心病患者中随冠心病的病情及冠状动脉粥样硬化的严重程度增加而表达逐渐增加，提示NLRP3及其下游炎症因子可能与冠心病的病情及动脉粥样硬化病变严重程度相关；2. NLRP3及其下游炎症因子在急性ST段抬高型心肌梗死发病过程中具有动态变化，提示NLRP3及其下游炎症因子可能参与了急性ST段抬高型心肌梗死发病过程中的急性炎症反应；3.在人单核细胞和内皮细胞中都存在NLRP3及其下游炎症因子的表达，在脂蛋白的作用下能够表现出不同程度的活化和抑制作用，干预NLRP3炎症小体能够明显抑制细胞因子的产生，提示NLRP3炎症小体在参与动脉粥样硬化发生发展的多种细胞内表达，诱导炎症介质的释放，能够全面参与动脉粥样硬化发生发展过程中的炎症反应，干预NLRP3有可能成为防治动脉粥样硬化新的靶点。
Background: Coronary artery disease (CAD) is the leading cause of mortality inmost developed countries. Atherosclerosis, which is a progressive disorder of the vesselwalls with the formation of plaques throughout the arterial system, is the essentialpathological process of CAD. It is general accepted that a complex endothelialdysfunction induced by free radicals, low density lipoproteins (LDL), infectiousmicroorganisms, shear stress, toxins, hypertension or a combination of these and otherfactors will lead to an chronic inflammatory response which leads to atherosclerosis.Chronic inflammation is recognized as a major driving force in atherogenesis. The sitesof atherosclerotic plaque development in the arterial wall are characterized bycholesterol accumulation and infiltration of peripheral blood monocytes, whichgradually differentiate into macrophages.
Pattern recognition receptor (PRR)-mediated signaling pathways have recentlybeen elucidated to bridge innate immune system and atherosclerosis, they can detectpathogen-associated molecular patterns (PAMPs) and endogenous danger signals(DAMPs). Once activated, the monocytes and macrophages secrete a myriad ofcytokines that promote inflammation in the arterial wall. NOD-like receptor family,pyrin domain containing3(NLRP3) is a member of the NLR family. Upon activation,NLRP3recruits the adapter protein and forms NLRP3inflammasome. The NLRP3inflammasome assembles in response to a variety of exogenous and endogenousactivators as an initial priming step，and thereby initiates IL-1β and I-18processing, akey step in the innate immune response. As the role of NLRP3inflamasome in humanatherosclerosis is unclear yet, confirm potential role of NLRP3inflamasome in thedevelopment of atherosclerosis will provide a new theoretical basis for the innateimmune system participating in atherosclerosis development and highlight the potentialof NLRP3inflammasome as a target for prevention and treatment of atherosclerosis.
Method: There are two parts in this study: the first part we observed theexpression of NLRP3and downstream cytokines in patients with CAD by ELISA,real-time PCR and Western Blot. Sixty-four CAD patients (patients with stable anginaand unstable angina) and twenty healthy controls were enrolled in this study. In addition,thirty patients with STEMI were recruited in this study. The expression levels ofNLRP3and downstream cytokines were determined at four different time points: within6hours after symptom onset (3.5±1.1h), acute phase at48~72hours (57.0±9.4h),convalescence stage at1week (7±1d) and stable period at4~6weeks (5.1±0.7w); thesecond part we study the role of NLRP3on the cell level, ox-LDL、HDL、ox-HDL wereused to stimulate human mononuclear cell line (Thp-1) and human umbilical veinendothelial cell line (ECV304), then expression of NLRP3and downstream cytokineswere observed. The following, we used NLRP3siRNA to down regulate the NLRP3mRNA expression, again gave ox-LDL、HDL and ox-HDL act on human mononuclearcell line Thp-1, observed the activation of NLRP3and downstream caspase-1、IL-1βandIL-18.
Results:1. These results showed that the expression of NLRP3and downstreamcytokines gradually increased along with the increasing severity of CAD;2. NLRP3anddownstream cytokines had a dynamic variation in patients with STEMI;3. ox-LDL、ox-HDL acted on mononuclear cells can promote the NLRP3expression, and furtheractivated the downstream caspase-1, inducd the secretion of IL-1β and IL-18; theactivation effect was concentration dependent, NLRP3and downstream cytokinesdecreased with the treatment of HDL;4.The mRNA and protein expression of NLRP3and downstream cytokines were existed in human umbilical vein endothelial cells(ECV304), ox-LDL and ox-HDL can promote the expression of NLRP3and release ofdownstream IL-1β and IL-18;5. Intervention with NLRP3inflammasome couldsignificantly inhibit the release of downstream IL-1β and IL-18.
Conclusion：1. the expression of NLRP3and downstream cytokines graduallyincreased along with the increasing severity of CAD, indicating that NLRP3anddownstream cytokines might be relevant with the severity of CAD；2. NLRP3anddownstream cytokines had a dynamic variation in STEMI, indicating that NLRP3anddownstream cytokines might be involved in the acute inflamatory response of STEMI；3.Lipoprotein acted on human mononuclear cells and endothelial cells can showdifferent degree of activation and inhibition, NLRP3expressed in a variety of cells,inducing the release of inflammatory mediators, fully participated in the occurrence and development of atherosclerosis.
引文
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[28]Sun HY, Wang NP (2005) Hypoxic postconditioning reduces cardiomyocyte lossby inhibiting ROS generation and intracellular Ca2+overload. Am J Physiol HeartCirc Physiol288:H1900-1908.
[29]Rubartelli A (2012) Redox control of NLRP3inflammasome activation in healthand disease. J Leukoc Biol92:951-958.
[30]Zhou R, Yazdi AS (2011) A role for mitochondria in NLRP3inflammasomeactivation. Nature469:221-225.
[31]Segovia J, Sabbah A (2012) TLR2/MyD88/NF-κB pathway, reactive oxygenspecies, potassium efflux activates NLRP3/ASC inflammasome during respiratorysyncytial virus infection. PLoS One7:e29695.
[32]Jin C, Frayssinet P (2011) NLRP3inflammasome plays a critical role in thepathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci U S A108:14867-14872.
[1] Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis.Annu Rev Immunol27:165–197.
[2] Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: Pathogenic and regulatorypathways. Physiol Rev86:515–581.
[3] Akira S, Uematsu S (2006) Pathogen recognition and innate immunity. Cell124:783-801.
[4] Michelsen K S, Doherty T M (2004) Role of Toll-like receptors in atherosclerosis.Circ Res95:96-97.
[5] Methe H, Kim J O (2005) Expansion of circulating Toll-like receptor4positivemonocytes in patients with acute coronary syndrome. Circulation111:2654-2661.
[6] Chavez-Sanchez L, Madrid-Miller A (2010) Activation of TLR2and TLR4byminimally modified low-density lipoprotein in human macrophages and monocytestriggers the inflammatory response. Hum Immunol71:737-744.
[7] Grenier D, Grignon L (2006) Response of human macrophage-like cells tostimulation by Fusobacterium nucleatum ssp. nucleatum lipopolysaccharide. OralMicrobiol Immunol21:190-196.
[8] den Dekker WK, Cheng C, Pasterkamp G (2010) Toll like receptor4inatherosclerosis and plaque destabilization. Atherosclerosis209:314-320.
[9]马林,曲鹏（2006）TLR4/NF-κB信号通路在血管成形术后再狭窄过程中的作用.中国动脉粥样硬化杂志7:50-54.
[10]牛楠,曲鹏（2008）阿托伐他汀降低急性冠脉综合征患者外周血CD_(14)~+单核细胞表面TLR4的表达.中华高血压杂志5：52-56.
[11]丁彦春，曲鹏（2007）核苷酸结合的寡聚结构域2激动剂与Toll样受体激动剂协同诱导血管平滑肌细胞合成促炎症细胞因子.中华高血压杂志15：1017-1021.
[12]Duewell P, Kono H (2010) NLRP3inflammasomes are required for atherogenesisand activated by cholesterol crystals. Nature464:1357-1361.
[13]Menu, Pellegrin M (2011) Atherosclerosis in ApoE-deficient mice progressesindependently of the NLRP3inflammasome. Cell Death and Disease2:e137.
[14]Hoffman H M, Brydges S D (2011) Genetic and molecular basis ofinflammasome-mediated disease. J Biol Chem286:10889-10896.
[15]Ait-Oufella H, Taleb S (2011) Recent advances on the role of cytokines inatherosclerosis. Arterioscler Thromb Vasc Biol31:969-979.
[16]Ragino YI, Chernyavski AM (2012) Activity of the inflammatory process indifferent types of unstable atherosclerotic plaques. Bull Exp Biol Med153:186-189.
[17]Ma Yu, Ni Wen (2010) Effect of repeated ischaemic preconditioning on TLR4andproinflammatory cytokines TNF-α and IL-1β in myocardial ischaemia-reperfusioninjury in a rat model. Arch Med Sci6:843-847.
[18]Jawień J, Olszanecki R (2012) Apolipoprotein E knockout mice: an experimentalmodel to study inflammatory mechanisms of atherosclerosis and to screen aputative anti-atherogenic properties of drugs. Centr Eur J Immunol37:36-44.
[19]G men AY Gümü lü S (2012) Paraoxonase-1activity and the levels of lipids andlipid peroxidation markers in arterial versus venous blood samples in coronaryangiography patients. Postep Kardiol Inter3:199–204.
[20]González-Benítez JF, Juárez-Verdayes MA (2008) The NALP3/Cryopyrin-inflammasome complex is expressed in LPS-induced ocular inflammation.Mediators Inflamm.2008:614345.
[21]Muruve DA, Pétrilli V (2008) The inflammasome recognizes cytosolic microbialand host DNA and triggers an innate immune response. Nature452:103-107.
[22]Mariathasan S, Weiss DS (2006) Cryopyrin activates the inflammasome inresponse to toxins and ATP. Nature440:228-232.
[23]Rajamaki K, Lappalainen J (2010) Cholesterol crystals activate the NLRP3inflammasome in human macrophages: a novel link between cholesterolmetabolism and inflammation. PLoS One5: e11765.
[24]Jiang Y, Wang M (2012) Oxidized low-density lipoprotein induces secretion ofinterleukin-1β by macrophages via reactive oxygen species-dependent NLRP3inflammasome activation. Biochem Biophys Res Commun425:121-126.
[25]Xiong YS, Yu J (2013) The Role of Siglec-1and SR-BI Interaction in thePhagocytosis of Oxidized Low Density Lipoprotein by Macrophages. PLoS One8:e58831.
[26]Su X, Ao L, Shi Y (2011) Oxidized low density lipoprotein induces bonemorphogenetic protein-2in coronary artery endothelial cells via Toll-like receptors2and4. J Biol Chem286:12213-12220.
[27]Mitra S, Goyal T (2011) Oxidized LDL, LOX-1and atherosclerosis. CardiovascDrugs Ther.25:419-429.
[28]王虹艳,曲鹏(2005) TLR4/NF-κB信号和LOX-1对内皮细胞黏附功能的影响.中华心血管杂志10:827-832.
[29]S harma N, Desigan B (1999) The role of oxidized HDL in monocyte/macrophagefunctions in the pathogenesis of atherosclerosis in Rhesus monkeys. Scand J ClinLab Invest59:215-225.
[30]Hurtado I, Fiol C (1996) In vitro oxidised HDL exerts a cytotoxic effect onmacrophages. Atherosclerosis125:39-46.
[31]Franceschini G (2011) Epidemiologic evidence for high density lipoproteincholesterol as a risk factor for coronary artery disease. AmJ Cardiol88:9213.
[32]Shaul PW (2003) Endothelial nitric oxide synthase, caveolae and the developmentof atherosclerosis. J Physiol547:21-33.
[33]Ansell BJ, Navab M (2003) Inflammatory/antiinflammatory properties ofhigh-density lipoprotein distinguish patients from control subjects better thanhigh-density lipoprotein cholesterol levels and are favorably affected by simvastatintreatment. Circulation108:2751-2756.
[34]Park SH, Park JH (2003) Involvement of transcription factors in plasma HDLprotection against TNF-alpha-induced vascular cell adhesion molecule-1expression.Int J Biochem Cell Biol35:168-182
[35]Chen K, Zhang J (2013) ATP-P2X4signaling mediates NLRP3inflammasomeactivation: A novel pathway of diabetic nephropathy. Int J Biochem Cell Biol45:932-943.
[36]Yin Y, Yan Y (2011) Inflammasomes are differentially expressed in cardiovascularand other tissues. Int J Immunopathol Pharmacol22:311-322.
[37]Kristiina R, Jani L (2010) Cholesterol Crystals Activate the NLRP3Inflammasomein Human Macrophages: A Novel Link between Cholesterol Metabolism andInflammation. PLoS ONE5:e11765.
[38]Buttle DJ, Murata M (1992) CA074methyl ester: A proinhibitor for intracellularcathepsin B. Arch Biochem Biophys299:377–380.
[39]Halle A, Hornung V (2008) The NALP3inflammasome is involved in the innateimmune response to amyloid-beta. Nat Immunol9:857–865.
[40]Hornung V, Bauernfeind F (2008) Silica crystals and aluminum salts activate theNALP3inflammasome through phagosomal destabilization. Nat Immunol9:847–856.
[41]Tsai WH, Huang DY (2008) Dual roles of NOD2in TLR4-mediated signaltransduction and–induced inflammatory gene expression in macrophages. CellMicrobiol13:717-730.
[42]Petrili V, Papin S (2007) Activation of the NALP3inflammasome is triggered bylow intracellular potassium concentration. Cell Death Differ14:1583-1589.
[43]Rubartelli A (2012) Redox control of NLRP3inflammasome activation in healthand disease. J Leukoc Biol92:951-958.
[44]Zhou R, Yazdi AS (2011) A role for mitochondria in NLRP3inflammasomeactivation. Nature469:221-225.
[45]Segovia J, Sabbah A (2012) TLR2/MyD88/NF-κB pathway, reactive oxygenspecies, potassium efflux activates NLRP3/ASC inflammasome during respiratorysyncytial virus infection. PLoS One7:e29695.
[46]Jin C, Frayssinet P (2011) NLRP3inflammasome plays a critical role in thepathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci U S A108:14867-14872.
[47]Dostert C, Petrilli V (2008) Innate immune activation through Nalp3inflammasome sensing of asbestos and silica. Science320:674-67728.
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[20] Duewell P, Kono H, Rayner K J, et al. NLRP3inflammasomes are required foratherogenesis and activated by cholesterol crystals[J]. Nature,2010,464(7293):1357-1361.
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[22] Tsai W H, Huang D Y, Yu Y H, et al. Dual roles of NOD2in TLR4-mediatedsignal transduction and-induced inflammatory gene expression in macrophages[J].Cell Microbiol,2011,13(5):717-730.
[23]丁彦春,曲鹏.核苷酸结合的寡聚结构域2激动剂与Toll样受体激动剂协同诱导血管平滑肌细胞合成促炎症细胞因子[J].中华高血压杂志,2007,15(12):1017-1021.
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[2] Hansson GK, Libby P (2006) The immune response in atherosclerosis: adouble-edged sword. Nat Rev Immunol6:508–519.
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[5] Akira S, Uematsu S (2006) Pathogen recognition and innate immunity. Cell124:783-801.
[6] Cassel SL, Joly S (2009) The NLRP3inflammasome: a sensor of immune dangersignals. Semin Immunol21:194-198.
[7] Duewell P, Kono H (2010) NLRP3inflammasomes are required for atherogenesisand activated by cholesterol crystals. Nature464:1357-1361.
[8] Tangi TN, Elmabsout AA (2012) Role of NLRP3and CARD8in the regulation ofTNF-α induced IL-1β release in vascular smooth muscle cells. Int J Mol Med30:697-702.
[9] Rajamaki K, Lappalainen J (2010) Cholesterol crystals activate the NLRP3inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One5:e11765.
[10]中华医学会心血管病学分会（2007）中国慢性稳定性心绞痛诊断与治疗指南.中华心血管病杂志.35:195-206.
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[13]Gensini MD,Goffredo G （1983）A more meaningful scoring system for determining the severity of coronary heart disease. Circulation51:606.
[14]Hoffman H M, Brydges S D (2011) Genetic and molecular basis ofinflammasome-mediated disease. J Biol Chem286:10889-10896.
[15]Ait-Oufella H, Taleb S (2011) Recent advances on the role of cytokines inatherosclerosis. Arterioscler Thromb Vasc Biol31:969-979.
[16]Ragino YI, Chernyavski AM (2012) Activity of the inflammatory process indifferent types of unstable atherosclerotic plaques. Bull Exp Biol Med153:186-189.
[17]Ma Yu, Ni Wen (2010) Effect of repeated ischaemic preconditioning on TLR4andproinflammatory cytokines TNF-α and IL-1β in myocardial ischaemia-reperfusioninjury in a rat model. Arch Med Sci6:843-847.
[18]Jawień J, Olszanecki R (2012) Apolipoprotein E knockout mice: an experimentalmodel to study inflammatory mechanisms of atherosclerosis and to screen aputative anti-atherogenic properties of drugs. Centr Eur J Immunol37:36-44.
[19]G men AY, Gümü lü S (2012) Paraoxonase-1activity and the levels of lipids andlipid peroxidation markers in arterial versus venous blood samples in coronaryangiography patients. Postep Kardiol Inter3:199–204.
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[22]Menu, Pellegrin M (2011) Atherosclerosis in ApoE-deficient mice progressesindependently of the NLRP3inflammasome. Cell Death and Disease2:e137.
[23]Zuurbier CJ, Jong WM (2012) Deletion of the innate immune NLRP3receptorabolishes cardiac ischemic preconditioning and is associated with decreasedIl-6/STAT3signaling. PLoS One7:e40643.
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[26]Petrili V, Papin S (2007) Activation of the NALP3inflammasome is triggered bylow intracellular potassium concentration. Cell Death Differ14:1583-1589.
[27]Vanden Hoek TL, Becker LB (1998) Reactive oxygen species released frommitochondria during brief hypoxia induce preconditioning incardiomyocytes. J BiolChem273:18092-8.
[28]Sun HY, Wang NP (2005) Hypoxic postconditioning reduces cardiomyocyte lossby inhibiting ROS generation and intracellular Ca2+overload. Am J Physiol HeartCirc Physiol288:H1900-1908.
[29]Rubartelli A (2012) Redox control of NLRP3inflammasome activation in healthand disease. J Leukoc Biol92:951-958.
[30]Zhou R, Yazdi AS (2011) A role for mitochondria in NLRP3inflammasomeactivation. Nature469:221-225.
[31]Segovia J, Sabbah A (2012) TLR2/MyD88/NF-κB pathway, reactive oxygenspecies, potassium efflux activates NLRP3/ASC inflammasome during respiratorysyncytial virus infection. PLoS One7:e29695.
[32]Jin C, Frayssinet P (2011) NLRP3inflammasome plays a critical role in thepathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci U S A108:14867-14872.
[1] Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis.Annu Rev Immunol27:165–197.
[2] Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: Pathogenic and regulatorypathways. Physiol Rev86:515–581.
[3] Akira S, Uematsu S (2006) Pathogen recognition and innate immunity. Cell124:783-801.
[4] Michelsen K S, Doherty T M (2004) Role of Toll-like receptors in atherosclerosis.Circ Res95:96-97.
[5] Methe H, Kim J O (2005) Expansion of circulating Toll-like receptor4positivemonocytes in patients with acute coronary syndrome. Circulation111:2654-2661.
[6] Chavez-Sanchez L, Madrid-Miller A (2010) Activation of TLR2and TLR4byminimally modified low-density lipoprotein in human macrophages and monocytestriggers the inflammatory response. Hum Immunol71:737-744.
[7] Grenier D, Grignon L (2006) Response of human macrophage-like cells tostimulation by Fusobacterium nucleatum ssp. nucleatum lipopolysaccharide. OralMicrobiol Immunol21:190-196.
[8] den Dekker WK, Cheng C, Pasterkamp G (2010) Toll like receptor4inatherosclerosis and plaque destabilization. Atherosclerosis209:314-320.
[9]马林,曲鹏（2006）TLR4/NF-κB信号通路在血管成形术后再狭窄过程中的作用.中国动脉粥样硬化杂志7:50-54.
[10]牛楠,曲鹏（2008）阿托伐他汀降低急性冠脉综合征患者外周血CD_(14)~+单核细胞表面TLR4的表达.中华高血压杂志5：52-56.
[11]丁彦春，曲鹏（2007）核苷酸结合的寡聚结构域2激动剂与Toll样受体激动剂协同诱导血管平滑肌细胞合成促炎症细胞因子.中华高血压杂志15：1017-1021.
[12]Duewell P, Kono H (2010) NLRP3inflammasomes are required for atherogenesisand activated by cholesterol crystals. Nature464:1357-1361.
[13]Menu, Pellegrin M (2011) Atherosclerosis in ApoE-deficient mice progressesindependently of the NLRP3inflammasome. Cell Death and Disease2:e137.
[14]Hoffman H M, Brydges S D (2011) Genetic and molecular basis ofinflammasome-mediated disease. J Biol Chem286:10889-10896.
[15]Ait-Oufella H, Taleb S (2011) Recent advances on the role of cytokines inatherosclerosis. Arterioscler Thromb Vasc Biol31:969-979.
[16]Ragino YI, Chernyavski AM (2012) Activity of the inflammatory process indifferent types of unstable atherosclerotic plaques. Bull Exp Biol Med153:186-189.
[17]Ma Yu, Ni Wen (2010) Effect of repeated ischaemic preconditioning on TLR4andproinflammatory cytokines TNF-α and IL-1β in myocardial ischaemia-reperfusioninjury in a rat model. Arch Med Sci6:843-847.
[18]Jawień J, Olszanecki R (2012) Apolipoprotein E knockout mice: an experimentalmodel to study inflammatory mechanisms of atherosclerosis and to screen aputative anti-atherogenic properties of drugs. Centr Eur J Immunol37:36-44.
[19]G men AY Gümü lü S (2012) Paraoxonase-1activity and the levels of lipids andlipid peroxidation markers in arterial versus venous blood samples in coronaryangiography patients. Postep Kardiol Inter3:199–204.
[20]González-Benítez JF, Juárez-Verdayes MA (2008) The NALP3/Cryopyrin-inflammasome complex is expressed in LPS-induced ocular inflammation.Mediators Inflamm.2008:614345.
[21]Muruve DA, Pétrilli V (2008) The inflammasome recognizes cytosolic microbialand host DNA and triggers an innate immune response. Nature452:103-107.
[22]Mariathasan S, Weiss DS (2006) Cryopyrin activates the inflammasome inresponse to toxins and ATP. Nature440:228-232.
[23]Rajamaki K, Lappalainen J (2010) Cholesterol crystals activate the NLRP3inflammasome in human macrophages: a novel link between cholesterolmetabolism and inflammation. PLoS One5: e11765.
[24]Jiang Y, Wang M (2012) Oxidized low-density lipoprotein induces secretion ofinterleukin-1β by macrophages via reactive oxygen species-dependent NLRP3inflammasome activation. Biochem Biophys Res Commun425:121-126.
[25]Xiong YS, Yu J (2013) The Role of Siglec-1and SR-BI Interaction in thePhagocytosis of Oxidized Low Density Lipoprotein by Macrophages. PLoS One8:e58831.
[26]Su X, Ao L, Shi Y (2011) Oxidized low density lipoprotein induces bonemorphogenetic protein-2in coronary artery endothelial cells via Toll-like receptors2and4. J Biol Chem286:12213-12220.
[27]Mitra S, Goyal T (2011) Oxidized LDL, LOX-1and atherosclerosis. CardiovascDrugs Ther.25:419-429.
[28]王虹艳,曲鹏(2005) TLR4/NF-κB信号和LOX-1对内皮细胞黏附功能的影响.中华心血管杂志10:827-832.
[29]S harma N, Desigan B (1999) The role of oxidized HDL in monocyte/macrophagefunctions in the pathogenesis of atherosclerosis in Rhesus monkeys. Scand J ClinLab Invest59:215-225.
[30]Hurtado I, Fiol C (1996) In vitro oxidised HDL exerts a cytotoxic effect onmacrophages. Atherosclerosis125:39-46.
[31]Franceschini G (2011) Epidemiologic evidence for high density lipoproteincholesterol as a risk factor for coronary artery disease. AmJ Cardiol88:9213.
[32]Shaul PW (2003) Endothelial nitric oxide synthase, caveolae and the developmentof atherosclerosis. J Physiol547:21-33.
[33]Ansell BJ, Navab M (2003) Inflammatory/antiinflammatory properties ofhigh-density lipoprotein distinguish patients from control subjects better thanhigh-density lipoprotein cholesterol levels and are favorably affected by simvastatintreatment. Circulation108:2751-2756.
[34]Park SH, Park JH (2003) Involvement of transcription factors in plasma HDLprotection against TNF-alpha-induced vascular cell adhesion molecule-1expression.Int J Biochem Cell Biol35:168-182
[35]Chen K, Zhang J (2013) ATP-P2X4signaling mediates NLRP3inflammasomeactivation: A novel pathway of diabetic nephropathy. Int J Biochem Cell Biol45:932-943.
[36]Yin Y, Yan Y (2011) Inflammasomes are differentially expressed in cardiovascularand other tissues. Int J Immunopathol Pharmacol22:311-322.
[37]Kristiina R, Jani L (2010) Cholesterol Crystals Activate the NLRP3Inflammasomein Human Macrophages: A Novel Link between Cholesterol Metabolism andInflammation. PLoS ONE5:e11765.
[38]Buttle DJ, Murata M (1992) CA074methyl ester: A proinhibitor for intracellularcathepsin B. Arch Biochem Biophys299:377–380.
[39]Halle A, Hornung V (2008) The NALP3inflammasome is involved in the innateimmune response to amyloid-beta. Nat Immunol9:857–865.
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