miR-155在冠心病患者中的表达及对小鼠巨噬细胞凋亡的影响

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英文题名：The Expression of microRNA-155in Patients of Coronary Heart Disease and Its Effects to Murine Macrophage Apoptosis 作者：朱国富 论文级别：博士 学科专业名称：内科学 中文关键词：miR-155 ; 动脉粥样硬化 ; Gensini评分 ; FADD ; 巨噬细胞凋亡 英文关键词：miR-155 ; atherosclerosis ; Gensini score ; FADD ; Macrophage apoptosis 学位年度：2013 导师：杨丽霞 学科代码：100201 学位授予单位：第三军医大学 论文提交日期：2013-10-01 答辩委员会主席：曾智

摘要

研究背景及目的：动脉粥样硬化性心血管疾病是全球发病率和死亡率居首位的疾病。大量的证据表明炎症和免疫反应在动脉粥样硬化(atherosclerosis,AS)的发生发展中有举足轻重的作用，从脂纹的形成到最终急性冠脉综合征(acute coronarysyndromes,ACS)的发生。小分子RNA(MicroRNAs,miRNAs)已被证明参与炎症和免疫反应。 miRNAs是长度为18-22个核苷酸的非编码RNA分子，通过抑制蛋白翻译或引起mRNA降解，从而在转录后水平调控基因的表达。在众多的miRNA，炎症相关的miRNA microRNA-155(miR-155)已被发现参与动脉粥样硬化。
     目前认为AS为体内外多种因素综合作用的结果，凋亡的增加为其中的因素之一，而凋亡增加确切的分子机制尚不明确。巨噬细胞凋亡已被证实为进展期动脉粥样硬化斑块的一个突出特点。进展期动脉粥样硬化病变的大量病理研究提示：巨噬细胞凋亡和大的坏死核心密切相关，并最终促进斑块破裂和急性血管事件。氧化型低密度脂蛋白(Oxidized low-density lipoprotein,OxLDL)是一个重要的动脉粥样硬化致病因子，也是一个潜在的细胞凋亡诱导剂。以前的研究已经表明，OxLDL诱导了多种组织和细胞的凋亡，包括内皮细胞，平滑肌细胞和巨噬细胞。一个由死亡受体家族，主要涉及Fas/FasL的信号和下游的caspase-3，介导的外源性凋亡途径，已被认为是OxLDL介导的细胞凋亡的机制之一。由于巨噬细胞凋亡在动脉粥样硬化和斑块不稳定中起着重要作用，细胞凋亡的调节可对进展期动脉粥样硬化斑块破裂提供显著的保护。越来越多的证据表明，细胞凋亡可由miRNA调控。作为一个多功能的miRNA，miR-155被证实参与免疫反应和细胞凋亡通路的调节。
     miR-155和动脉粥样硬化疾病的进展之间的关系目前还不清楚。这项研究首先旨在研究miR-155与冠状动脉狭窄病变的严重程度及斑块稳定性的关系。此外，鉴于其在凋亡途径中的重要作用，我们推测miR-155在OxLDL诱导的巨噬细胞凋亡中扮演重要角色。因此，本研究的主要目的是为了证明miR-155在OxLDL诱导的巨噬细胞凋亡中的作用及其具体机制。
     研究方法：(1)我们收集了110例疑似冠心病(coronary heart disease,CHD)患者，行冠状动脉CTA及冠状动脉造影检查冠脉病变情况，根据冠状动脉造影结果进行Gensini评分，评估冠状动脉狭窄病变的严重程度和范围；根据冠状动脉CTA评估斑块稳定性采用实时定量PCR方法检测了新鲜分离的外周血单个核细胞(peripheral bloodmonouclear cell,PBMCs)和血浆中miR-155的表达。(2)用不同浓度及时间梯度的OxLDL处理RAW264.7细胞，采用实时定量PCR方法检测miR-155的表达水平。(3)miR-155的模拟物，miR-155的抑制剂和阴性对照被瞬时转染入RAW264.7细胞或HEK-293细胞以实现miR-155的表达水平的上调或下调。或FADD表达载体被用来感染RAW264.7细胞以实现FADD表达水平的上调。(4)我们采用细胞活力实验(细胞计数试剂盒-8)检测oxLDL处理过的RAW264.7细胞的活力。(5)采用TUNEL法、双染色流式法(Annexin V/PI)和caspase-3的活化片段(17kDa)的蛋白表达等方法评估巨噬细胞凋亡。(6)采用生物信息学技术预测miR-155的潜在靶标。(7)采用荧光素酶实验来验证假定的miR-155靶标。(8)免疫印迹法(WB)用于检测caspase-3和FADD的蛋白表达水平。研究结果：(1)56例冠心病患者PBMCs及血浆中miR-155的表达水平明显低于54
     例非冠心病患者(P <0.01)。(2)不稳定性心绞痛组(unstable angina pectoris, UAP,n=31)和急性心梗组(acute myocardial infarction,AMI,n=24)患者PBMCs及血浆中miR-155的水平明显低于胸痛综合征组(chest pain syndrome,CPS，n=31)组，而稳定性心绞痛组(stable angina pectoris,SAP，n=24)和CPS组患者之间无统计学差异。(3)Spearman相关分析表明，血浆中miR-155的表达水平与PBMCs中miR-155的表达水平呈正相关(4)有2支或大于等于3支病变血管患者的miR-155水平明显低于0和1支病变血管的患者。0支和1支病变血管的患者之间miR-155的水平没有显着差异。(5)miR-155水平与Gensini积分呈负相关(r=-0.663，P <0.001)。(6)软斑块组miR-155的表达水平较纤维斑块组及钙化斑块组降低(P<0.05)。(7)miR-155的表达水平与年龄(r=-0.227)、高血压(R=-0.440)、总胆固醇(R=0.239)、高密度脂蛋白(HDL)胆固醇(R=0.280)、低密度脂蛋白(LDL)胆固醇(r=-0.315)、吸烟(R=-0.363)、血管紧张素转换酶抑制剂(R=-0.250)、他汀类药物(r=-0.368)，高敏C-反应蛋白(hs-CRP)(r=-0.515)等相关。(8)OxLDL以剂量和时间依赖方式增加RAW264.7细胞中miR-155的表达。(9)OxLDL能显著增加RAW264.7细胞凋亡，miR-155模拟物能抑制此作用，而miR-155的拮抗剂能抵消miR-155的抗凋亡作用。(10)生物信息学分析显示FADD可能为miR-155的直接靶标。(11)萤光素酶报告基因检测和WB实验进一步证实miR-155直接通过作用于FADD的3'-UTR区域从而抑制FADD表达。(12)miR-155抑制oxLDL诱导的细胞凋亡，但FADD过表达限制了miR-155的抗凋亡活性。
     研究结论：miR-155的表达水平与复杂的致动脉粥样硬化的代谢危险因素、冠状动脉狭窄病变的严重程度(由Gensini积分评估)、斑块稳定性(由冠脉CTA评估)呈负相关，提示miR-155在动脉粥样硬化进展中起保护作用。此外，我们的研究结果表明，miR-155通过作用于其靶标FADD，抑制oxLDL诱导的RAW264.7细胞凋亡，可望提供一种新的动脉粥样硬化的治疗方式。
Background and Objective: Atherosclerotic cardiovascular disease is the leadingcause of morbidity and mortality worldwide. A large amount of evidence supports a pivotalrole of inflammation and immune responses in all phases of atherosclerosis(AS), frominitiation of the fatty streak to final breakout of acute coronary syndromes (ACS).MicroRNAs (miRNAs) have been demonstrated to be associated with inflammation andimmune responses. miRNAs are18-22nucleotide long non-coding RNA molecules thatregulate gene expression posttranscriptionally by triggering either translation repression orRNA degradation. Among various miRNA, inflammation-related miRNAs-microRNA-155(miR-155) have been found to be involved in the atherogenesis.
     The etiology of AS is ascribed to various factors, one of which is the increase inapoptosis. The underlying molecular mechanisms of the increase in apoptosis remainlargely unknown. Macrophage apoptosis has been identified as a prominent feature ofadvanced atherosclerotic plaques. Pathological studies of advanced atherosclerotic lesionshave revealed a strong correlation between macrophage apoptosis and large necrotic cores,thought to promote plaque rupture and acute vascular events. Oxidized low-densitylipoprotein (OxLDL) is an important pathogenetic factor in atherosclerosis and a potentialinducer of cell apoptosis. Previous studies have demonstrated OxLDL-induced apoptosis ina variety of tissues and cells, including endothelial cells, smooth muscle cells (SMCs) andmacrophages. An extrinsic pathway mediated by the death receptor family, mainlyinvolving Fas/FasL signaling and down-stream caspase-3, has been defined as theunderlying mechanism in OxLDL-mediated apoptosis. Since macrophage apoptosis playsan important role in atherogenesis and plaque destabilization, modulation of cell death mayprovide significant protection against advanced atherosclerotic plaque rupture. Accumulating evidence indicates that the apoptotic machinery is regulated by miRNAs. Asa multi-functional miRNA, miR-155was previously shown to participate in the regulationof immunological responses and apoptotic pathways.
     The relationship between miR-155and the progression of atherosclerotic diseases isunclear. This study first aimed to investigate the association between miR-155and theseverity and extent of coronary stenotic lesions and atherosclerotic plaques stability.Moreover,given its crucial involvement in apoptotic pathways, we hypothesized thatmiR-155plays a role in oxLDL-induced macrophage apoptosis. Accordingly, the primaryaim of the current study was to address the specific role of miR-155in oxLDL-inducedmacrophage apoptosis and clarify the underlying mechanisms.
     Methods:(1) We measured the miR-155expression in both freshly isolated peripheralblood monouclear cell (PBMCs) and plasma by real-time PCR in110consecutive patientsundergoing coronary computed tomography angiography (CTA) and coronary angiographyfor suspected coronary heart disease (CHD). The severity and extent of coronary stenoticlesions were evaluated on coronary angiography findings by Gensini score and the plaquesstability was evaluated on coronary CTA.(2) qRT-PCR was performed to detect miR-155expression in oxLDL-treated RAW264.7cells.(3) miR-155mimics, miR-155inhibitor,andnegative control were transiently transfected into RAW264.7cells or HEK-293cells to up-or down-regulate the miR-155expression level. Or the fas-associated deathdomain-containing protein (FADD)-expressing vector was used to infect RAW264.7cellsto up-regulate the FADD expression level.(4)Cell viability assays (Cell Counting Kit-8)was performed in oxLDL-treated RAW264.7cells,with or without transfection of miR-155mimics/inhibitor.(5) TUNEL assay, Annexin V/propidium iodide (PI) staining,andcleaved caspase-3(17kDa) protein expression were used to assess the macrophageapoptosis.(6) Bioinformatics technique was used to predict the potential target of miR-155.(7) Luciferase assays was performed to validate the putative miR-155target.(8) Westernblotting (WB) was used to detect caspase-3and FADD protein expression.
     Results:(1)The miR-155expression was significantly lower in56patients with CHDthan those in54controls (p <0.01).(2) The level of miR-155in PBMCs or plasma waslower in patients with unstable angina pectoris (UAP,n=31) and acute myocardial infarction(AMI,n=24) than in patients with chest pain syndrome (CPS,n=31), while no statistically significant differences were observed between patients with stable angina pectoris(SAP,n=24) and CPS.(3) Spearman’s correlation analysis showed that the expression ofmiR-155in plasma positively correlated with the expression in PBMCs.(4) The levels ofmiR-155in the subjects with diseased vessels of2and>=3were significantly lower thanthose with diseased vessel of0and1. The levels of miR-155were not significantlydifferent among groups with diseased vessels of0and1.(5) miR-155were negativelyassociated with Gensini scores(r=-0.663,p<0.001).(6) The miR-155level in patiens of softplaque is significantly lower than those with calcified plaque and fibrous plaque.(7) ThemiR-155expression was significantly correlated to age (r=-0.227), hypertension (r=-0.440),total cholesterol (r=0.239), high-density lipoprotein (HDL) cholesterol (r=0.280),low-density lipoprotein(LDL) cholesterol (r=-0.315), tobacco (r=-0.363),ACEI (r=-0.250),statins(r=-0.368)，high sensitivity C-reactive protein (hs-CRP)(r=-0.515).(8) Constitutiveexpression of miR-155in RAW264.7cells was increased following stimulation withOxLDL in a dose-and time-dependent manner.(9) OxLDL-treated RAW264.7cells showeda marked increase in apoptosis, which was suppressed in the presence of miR-155mimicsand increased with antagonists of miR-155.(10) Bioinformatics analysis revealed FADD asa putative target of miR-155.(11) Luciferase reporter assay and WB further disclosed thatmiR-155inhibits FADD expression by directly targeting the3’-UTR region.(12) miR-155inhibits oxLDL-induced apoptosis, but overexpression of FADD limits this anti-apoptoticactivity.
     Conclusion: miR-155expression is inversely associated with complicatedproatherogenic metabolic risk factors, and the severity of coronary stenotic lesionscalculated by Gensini scores, supporting a protective role for miR-155against theprogression of atherosclerosis. Moreover,our results collectively suggest that miR-155attenuates apoptosis of OxLDL-mediated RAW264.7cells by targeting FADD, supporting apossible therapeutic role in atherosclerosis.

引文

1Pieper, K.S., et al., Validity of a risk-prediction tool for hospital mortality: the Global Registry of Acute CoronaryEvents. Am Heart J,2009.157(6): p.1097-105.
    2Glaser, R., et al., Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronaryintervention. Circulation,2005.111(2): p.143-9.
    3Schaar, J.A., et al., Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on thevulnerable plaque, June17and18,2003, Santorini, Greece. Eur Heart J,2004.25(12): p.1077-82.
    4Virmani, R., et al., Pathology of the vulnerable plaque. J Am Coll Cardiol,2006.47(8Suppl): p. C13-8.
    1Lee, R.C., R.L. Feinbaum, and V. Ambros, The C. elegans heterochronic gene lin-4encodes small RNAs withantisense complementarity to lin-14. Cell,1993.75(5): p.843-54.
    2Novina, C.D. and P.A. Sharp, The RNAi revolution. Nature,2004.430(6996): p.161-4.
    3Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell,2004.116(2): p.281-97.
    4Zhao, Y., E. Samal, and D. Srivastava, Serum response factor regulates a muscle-specific microRNA that targets Hand2during cardiogenesis. Nature,2005.436(7048): p.214-20.
    5Care, A., et al., MicroRNA-133controls cardiac hypertrophy. Nat Med,2007.13(5): p.613-8.
    6Yang, B., et al., The muscle-specific microRNA miR-1regulates cardiac arrhythmogenic potential by targeting GJA1and KCNJ2. Nat Med,2007.13(4): p.486-91.
    7van Rooij, E., et al., Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29in cardiacfibrosis. Proc Natl Acad Sci U S A,2008.105(35): p.13027-32.
    8Narula, J., et al., Mechanisms of disease: apoptosis in heart failure--seeing hope in death. Nat Clin Pract CardiovascMed,2006.3(12): p.681-8.
    9Chen, T., et al., MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9expression inoxLDL-stimulated monocyte/macrophages. Cardiovasc Res,2009.83(1): p.131-9.
    1Tam, W. and J.E. Dahlberg, miR-155/BIC as an oncogenic microRNA. Genes Chromosomes Cancer,2006.45(2): p.211-2.
    2Thai, T.H., et al., Regulation of the germinal center response by microRNA-155. Science,2007.316(5824): p.604-8.
    3Taganov, K.D., et al., NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signalingproteins of innate immune responses. Proc Natl Acad Sci U S A,2006.103(33): p.12481-6.
    4Zhu, N., et al., Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation andmigration. Atherosclerosis,2011.215(2): p.286-93.
    5Martin, M.M., et al., The human angiotensin II type1receptor+1166A/C polymorphism attenuates microrna-155binding. J Biol Chem,2007.282(33): p.24262-9.
    6Martin, M.M., et al., MicroRNA-155regulates human angiotensin II type1receptor expression in fibroblasts. J BiolChem,2006.281(27): p.18277-84.
    7O'Connell, R.M., et al., MicroRNA-155is induced during the macrophage inflammatory response. Proc Natl Acad SciU S A,2007.104(5): p.1604-9.
    8Huang, R.S., et al., MicroRNA-155Silencing Enhances Inflammatory Response and Lipid Uptake in OxidizedLow-Density Lipoprotein-Stimulated Human THP-1Macrophages. J Investig Med,2010.58(8): p.961-7.
    9Rossi, M.L., et al., Different quantitative apoptotic traits in coronary atherosclerotic plaques from patients with stableangina pectoris and acute coronary syndromes. Circulation,2004.110(13): p.1767-73.
    10Littlewood, T.D. and M.R. Bennett, Apoptotic cell death in atherosclerosis. Curr Opin Lipidol,2003.14(5): p.469-75.
    1Tabas, I., Apoptosis and plaque destabilization in atherosclerosis: the role of macrophage apoptosis induced bycholesterol. Cell Death Differ,2004.11Suppl1: p. S12-6.
    2Schrijvers, D.M., et al., Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaqueprogression and stability. Cardiovasc Res,2007.73(3): p.470-80.
    3Napoli, C., Oxidation of LDL, atherogenesis, and apoptosis. Ann N Y Acad Sci,2003.1010: p.698-709.
    4Salvayre, R., et al., Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta,2002.1585(2-3): p.213-21.
    5Chen, J., et al., Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells.Circ Res,2004.94(3): p.370-6.
    6Tili, E., et al., Modulation of miR-155and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation andtheir possible roles in regulating the response to endotoxin shock. J Immunol,2007.179(8): p.5082-9.
    1Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci US A,2008.105(30): p.10513-8.
    2D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    3Hedin, U., J. Roy, and P.K. Tran, Control of smooth muscle cell proliferation in vascular disease. Curr Opin Lipidol,2004.15(5): p.559-65.
    4O'Connell, R.M., et al., MicroRNA-155is induced during the macrophage inflammatory response. Proc Natl Acad SciU S A,2007.104(5): p.1604-9.
    5Zhu, J., et al., Regulation of microRNA-155in atherosclerotic inflammatory responses by targeting MAP3K10. PLoSOne,2012.7(11): p. e46551.
    1Donners, M.M., et al., Hematopoietic miR155deficiency enhances atherosclerosis and decreases plaque stability inhyperlipidemic mice. PLoS One,2012.7(4): p. e35877.
    1Gensini, G.G., A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol,1983.51(3): p.606.
    1Stahl, H.F., et al., miR-155inhibition sensitizes CD4+Th cells for TREG mediated suppression. PLoS One,2009.4(9):p. e7158.
    2Banerjee, A., et al., Micro-RNA-155inhibits IFN-gamma signaling in CD4+T cells. Eur J Immunol,2010.40(1): p.225-31.
    1Pottier, N., et al., Identification of keratinocyte growth factor as a target of microRNA-155in lung fibroblasts:implication in epithelial-mesenchymal interactions. PLoS One,2009.4(8): p. e6718.
    2Chen, T., et al., MicroRNA-155regulates lipid uptake, adhesion/chemokine marker secretion and SCG2expression inoxLDL-stimulated dendritic cells/macrophages. Int J Cardiol,2011.147(3): p.446-7.
    3D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    4Hoekstra, M., et al., The peripheral blood mononuclear cell microRNA signature of coronary artery disease. BiochemBiophys Res Commun,2010.394(3): p.792-7.
    5Nazari-Jahantigh, M., et al., MicroRNA-155promotes atherosclerosis by repressing Bcl6in macrophages. J ClinInvest,2012.122(11): p.4190-202.
    6Wang, L.G. and J. Gu, Serum microRNA-29a is a promising novel marker for early detection of colorectal livermetastasis. Cancer Epidemiol,2011.
    1Burgess, D.J., Glioblastoma: Microvesicles as major biomarkers? Nat Rev Cancer,2013.13(1): p.8.
    2Wang K, Z.S., Weber J, Baxter D, Galas DJ, Mammalian cells in culture actively export specific microRNAs. NaturePrecedings,2009.
    3Deregibus, M.C., et al., Endothelial progenitor cell derived microvesicles activate an angiogenic program inendothelial cells by a horizontal transfer of mRNA. Blood,2007.110(7): p.2440-8.
    4Wang, G.K., et al., Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardialinfarction in humans. Eur Heart J,2010.31(6): p.659-66.
    5Sabatine, M.S., et al., Prognostic significance of the Centers for Disease Control/American Heart Associationhigh-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronaryartery disease. Circulation,2007.115(12): p.1528-36.
    1Newby, A.C., Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaquerupture. Physiol Rev,2005.85(1): p.1-31.
    2Boyle, J.J., P.L. Weissberg, and M.R. Bennett, Human macrophage-induced vascular smooth muscle cell apoptosisrequires NO enhancement of Fas/Fas-L interactions. Arterioscler Thromb Vasc Biol,2002.22(10): p.1624-30.
    3Gautier, E.L., et al., Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage.Circulation,2009.119(13): p.1795-804.
    4Guo, R.W., et al., Stim1-and Orai1-mediated store-operated calcium entry is critical for angiotensin II-inducedvascular smooth muscle cell proliferation. Cardiovasc Res,2011.
    5Guo, R.W., et al., Angiotensin II induces NF-kappa B activation in HUVEC via the p38MAPK pathway. Peptides,2006.27(12): p.3269-75.
    1Gironella, M., et al., Tumor protein53-induced nuclear protein1expression is repressed by miR-155, and itsrestoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A,2007.104(41): p.16170-5.
    2Boullier, A., et al., Minimally oxidized LDL offsets the apoptotic effects of extensively oxidized LDL and freecholesterol in macrophages. Arterioscler Thromb Vasc Biol,2006.26(5): p.1169-76.
    1Tricot, O., et al., Relation between endothelial cell apoptosis and blood flow direction in human atheroscleroticplaques. Circulation,2000.101(21): p.2450-3.
    2Liu, J., et al., Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoproteinreceptor-null mice. Arterioscler Thromb Vasc Biol,2005.25(1): p.174-9.
    3van Reyk, D.M., W. Jessup, and R.T. Dean, Prooxidant and antioxidant activities of macrophages in metal-mediatedLDL oxidation: the importance of metal sequestration. Arterioscler Thromb Vasc Biol,1999.19(4): p.1119-24.
    4Bjorkerud, S. and B. Bjorkerud, Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatorycells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol,1996.149(2): p.367-80.
    5Tabas, I., Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance oflesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol,2005.25(11): p.2255-64.
    1Kolodgie, F.D., et al., Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death.Am J Pathol,2000.157(4): p.1259-68.
    2van Vlijmen, B.J., et al., Macrophage p53deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenicmice. Circ Res,2001.88(8): p.780-6.
    3Hutter, R., et al., Caspase-3and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis aslink between inflammation and atherothrombosis. Circulation,2004.109(16): p.2001-8.
    4Jovinge, S., et al., Human monocytes/macrophages release TNF-alpha in response to Ox-LDL. Arterioscler ThrombVasc Biol,1996.16(12): p.1573-9.
    5Hardwick, S.J., et al., Apoptosis in human monocyte-macrophages exposed to oxidized low density lipoprotein. JPathol,1996.179(3): p.294-302.
    6He, L. and G.J. Hannon, MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet,2004.5(7): p.522-31.
    7Martin, M.M., et al., The human angiotensin II type1receptor+1166A/C polymorphism attenuates microrna-155binding. J Biol Chem,2007.282(33): p.24262-9.
    8Zhu, N., et al., Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation andmigration. Atherosclerosis,2011.215(2): p.286-93.
    9Donners, M.M., et al., Hematopoietic miR155deficiency enhances atherosclerosis and decreases plaque stability inhyperlipidemic mice. PLoS One,2012.7(4): p. e35877.
    10Zhu, J., et al., Regulation of microRNA-155in atherosclerotic inflammatory responses by targeting MAP3K10. PLoSOne,2012.7(11): p. e46551.
    11Wei, Y., et al., The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1-andmicroRNA-155-Dependent Pathway During Atherosclerosis. Circulation,2013.127(15): p.1609-19.
    1Nazari-Jahantigh, M., et al., MicroRNA-155promotes atherosclerosis by repressing Bcl6in macrophages. J ClinInvest,2012.122(11): p.4190-202.
    2Gironella, M., et al., Tumor protein53-induced nuclear protein1expression is repressed by miR-155, and itsrestoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A,2007.104(41): p.16170-5.
    3Meng, W., et al., Anti-miR-155oligonucleotide enhances chemosensitivity of U251cell to taxol by inducing apoptosis.apoptosis. Cell Biol Int,2012.
    4Zheng, S.R., et al., Clinical significance of miR-155expression in breast cancer and effects of miR-155ASO on cellviability and apoptosis. Oncol Rep,2012.27(4): p.1149-55.
    5Kim, J.H., W.S. Kim, and C. Park, Epstein-Barr virus latent membrane protein-1protects B-cell lymphoma fromrituximab-induced apoptosis through miR-155-mediated Akt activation and up-regulation of Mcl-1. Leuk Lymphoma,2012.
    6Ovcharenko, D., et al., Genome-scale microRNA and small interfering RNA screens identify small RNA modulators ofof TRAIL-induced apoptosis pathway. Cancer Res,2007.67(22): p.10782-8.
    7Pottier, N., et al., Identification of keratinocyte growth factor as a target of microRNA-155in lung fibroblasts:implication in epithelial-mesenchymal interactions. PLoS One,2009.4(8): p. e6718.
    8Lu, C., et al., miR-221and miR-155regulate human dendritic cell development, apoptosis, and IL-12productionthrough targeting of p27kip1, KPC1, and SOCS-1. Blood,2011.117(16): p.4293-303.
    1Zadelaar, A.S., et al., Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice followingadenovirus-mediated Fas ligand gene transfer. Atherosclerosis,2005.183(2): p.244-50.
    2Nhan, T.Q., et al., The p17cleaved form of caspase-3is present within viable macrophages in vitro and inatherosclerotic plaque. Arterioscler Thromb Vasc Biol,2003.23(7): p.1276-82.
    3Ermak, N., et al., Role of reactive oxygen species and Bax in oxidized low density lipoprotein-induced apoptosis ofhuman monocytes. Atherosclerosis,2008.200(2): p.247-56.
    4Salvayre, R., et al., Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta,2002.1585(2-3): p.213-21.
    1Tili, E., et al., Modulation of miR-155and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation andtheir possible roles in regulating the response to endotoxin shock. J Immunol,2007.179(8): p.5082-9.
    2Zhang, Y., et al., Conditional Fas-associated death domain protein (FADD): GFP knockout mice reveal FADD isdispensable in thymic development but essential in peripheral T cell homeostasis. J Immunol,2005.175(5): p.3033-44.
    1Seo, S.M., et al., Correlations between the level of high-sensitivity c-reactive protein and cardiovascular risk factors inkorean adults with cardiovascular disease or diabetes mellitus: the CALLISTO study. J Atheroscler Thromb,2013.20(7):p.616-22.
    2Rus, H. and F.I. Niculescu, Inflammation, aspirin, and the risk of cardiovascular disease. N Engl J Med,1997.337(6):p.423; author reply423-4.
    3Berk, B.C., W.S. Weintraub, and R.W. Alexander, Elevation of C-reactive protein in "active" coronary artery disease.Am J Cardiol,1990.65(3): p.168-72.
    4何松清,江.,血清MMP-2、CRP水平对不稳定性心绞痛的诊断及预后判断价值.医学研究生学报,2001.14(4):p.316-8
    1曹相誉,杨.,李会利,血清C反应蛋白对不稳定型心绞痛近期预后的评价.疑难病杂志,20032(3): p.136-8
    2Rus, H. and F.I. Niculescu, Inflammation, aspirin, and the risk of cardiovascular disease. N Engl J Med,1997.337(6):p.423; author reply423-4.
    3中华医学会心血管病学分会,全国心绞痛及心肌缺血学术研讨会纪要.中华心血管病杂志,200028(6): p.405-8.
    4Wang, L., et al., Functional analysis of the C-reactive protein (CRP) gene-717A>G polymorphism associated withcoronary heart disease. BMC Med Genet,2009.10: p.73.
    5Lawlor, D.A., et al., The association of C-reactive protein and CRP genotype with coronary heart disease: findingsfrom five studies with4,610cases amongst18,637participants. PLoS One,2008.3(8): p. e3011.
    6Piechota, W.,[Correlation of high-sensitivity CRP concentration with the extent of coronary atherosclerosis in menwith symptoms of ischemic heart disease]. Pol Merkur Lekarski,2005.18(107): p.511-5.
    7王振义,李.,阮长耿,等,血栓与止血-基础理论与临床. M2版.上海:上海科学技术出版社,1996.:382.
    8徐辉,蔡.,夏明凯,等,冠心病患者血D2二聚体和血栓前体蛋白含量变化及其临床意义.新医学,200536(3):p.147.
    9杨颉,宫.,心绞痛和脑血栓病人止血与凝血分子标志物的检测.青岛大学医学院学报,,2001.37(4): p.337-8.
    10崔家玉,高.,王丽萍,等.,不稳定心绞痛血凝/纤溶系统变化临床研究.实用心脑肺血管病杂志,2003.
    11(1): p.8-11
    11Shitrit, D., et al., Role of ELISA D-dimer test in patients with unstable angina pectoris presenting at the emergencydepartment with a normal electrocardiogram. Am J Hematol,2004.77(2): p.147-50.
    12田华,尚.,房桂青.,肌钙蛋白T、C反应蛋白、D-二聚体在判定不稳定型心绞痛预后中的价值.山东医药,44(14): p.15-6.
    13Lowe, G.D., et al., Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heartdisease. Arterioscler Thromb Vasc Biol,2004.24(8): p.1529-34.
    1Pirillo, A., G.D. Norata, and A.L. Catapano, Treating high density lipoprotein cholesterol (HDL-C): quantity versusquality. Curr Pharm Des,2013.19(21): p.3841-57.
    2Young, C.E., R.H. Karas, and J.T. Kuvin, High-density lipoprotein cholesterol and coronary heart disease. Cardiol Rev,2004.12(2): p.107-19.
    3Kitamura, A., et al., Association between non-high-density lipoprotein cholesterol levels and the incidence of coronaryheart disease among Japanese: the Circulatory Risk in Communities Study (CIRCS). J Atheroscler Thromb,2011.18(6):p.454-63.
    4Sacks, F.M., The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heartdisease: expert group recommendations. Am J Cardiol,2002.90(2): p.139-43.
    5Rus, H. and F. Niculescu, Inflammatory response in unstable angina. Circulation,1999.100(19): p. e98.
    6Harb, T.S., et al., Association of C-reactive protein and serum amyloid A with recurrent coronary events in stablepatients after healing of acute myocardial infarction. Am J Cardiol,2002.89(2): p.216-21.
    7Ridker, P.M., et al., C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease inwomen. N Engl J Med,2000.342(12): p.836-43.
    1Zheng, G.H., H.Y. Chen, and S.Q. Xiong, Polymorphisms of-174G>C and-572G>C in the interleukin6(IL-6) geneand coronary heart disease risk: a meta-analysis of27research studies. PLoS One,2012.7(4): p. e34839.
    2Qi, X., et al., Plasma levels of IL-8predict early complications in patients with coronary heart disease afterpercutaneous coronary intervention. Jpn Heart J,2003.44(4): p.451-61.
    3Kanda, T., et al., Interleukin-8as a sensitive marker of unstable coronary artery disease. Am J Cardiol,1996.77(4): p.304-7.
    4Olivotti, L., et al., Maximal endothelial tissue plasminogen activator release is not impaired in patients with acutecoronary syndromes before heparin treatment. Blood Coagul Fibrinolysis,2001.12(4): p.261-7.
    5吕克,刘.,蒋绮年,不稳定性心绞痛患者血浆组织型纤溶酶原激活物含量变化及其在危险分层中的意义.苏州大学学报(医学版),200424(6): p.896.
    6Jansson, J.H., B.O. Olofsson, and T.K. Nilsson, Predictive value of tissue plasminogen activator mass concentration onlong-term mortality in patients with coronary artery disease. A7-year follow-up. Circulation,1993.88(5Pt1): p.2030-4.
    7Thompson, S.G., et al., Hemostatic factors and the risk of myocardial infarction or sudden death in patients with anginapectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med,1995.332(10): p.635-41.
    8Ridker, P.M., et al., Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet,1993.341(8854): p.1165-8.
    1Ekmekci, H., et al., Significance of vitronectin and PAI-1activity levels in carotid artery disease: comparison ofsymptomatic and asymptomatic patients. Minerva Med,2013.104(2): p.215-23.
    2马娜,张.,魏宏顺,等,冠心病血清胆红素浓度与cTnT、血栓素A2关系的研究.临床心血管病杂志,2004.20(10): p.627.
    3Defilippis, A.P., et al., Thromboxane A Generation, in the Absence of Platelet COX-1Activity, in Patients With andWithout Atherothrombotic Myocardial Infarction. Circ J,2013.
    4Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci US A,2008.105(30): p.10513-8.
    5D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    6Hoekstra, M., et al., The peripheral blood mononuclear cell microRNA signature of coronary artery disease. BiochemBiophys Res Commun,2010.394(3): p.792-7.
    7Ji, X., et al., Plasma miR-208as a biomarker of myocardial injury. Clin Chem,2009.55(11): p.1944-9.
    1Ai, J., et al., Circulating microRNA-1as a potential novel biomarker for acute myocardial infarction. BiochemBiophys Res Commun,2010.391(1): p.73-7.
    2Fichtlscherer, S., et al., Circulating microRNAs in patients with coronary artery disease. Circ Res,2010.107(5): p.677-84.
    3De Rosa, S., et al., Transcoronary concentration gradients of circulating microRNAs. Circulation,2011.124(18): p.1936-44.
    4张俊峰等,细胞外基质金属蛋白酶诱导因子与冠心病临床类型的关系.上海交通大学学报(医学版),2009.12-1431-03
    1Kaden, J.J., et al., Time-dependent changes in the plasma concentration of matrix metalloproteinase9after acutemyocardial infarction. Cardiology,2003.99(3): p.140-4.
    2Hayashidani, S., et al., Targeted deletion of MMP-2attenuates early LV rupture and late remodeling after experimentalmyocardial infarction. Am J Physiol Heart Circ Physiol,2003.285(3): p. H1229-35.
    3Brehm, B.R., et al., Comparison of circulating endothelin-1and big endothelin-1levels in unstable versus stableangina pectoris. J Cardiovasc Pharmacol,1998.31Suppl1: p. S90-3.
    4Chai, S.B., et al., Increased plasma levels of endothelin-1and urotensin-II in patients with coronary heart disease.Heart Vessels,2010.25(2): p.138-43.
    1Zhen, W., et al., A Study of the Relationships between Serum Calcitonin Gene-Related Peptide, Sex Hormone,Homocysteine and Coronary Heart Disease in Postmenopausal Women. Int J Biomed Sci,2006.2(1): p.42-8.
    2Kimmel, M., et al., Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrastinduced nephropathy by N-acetylcysteine or zinc--preliminary results. Nephrol Dial Transplant,2008.23(4): p.1241-5.
    3Omland, T., et al., Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronarysyndromes. J Am Coll Cardiol,2008.51(6): p.627-33.
    1Ross, R., Atherosclerosis--an inflammatory disease. N Engl J Med,1999.340(2): p.115-26.
    2Hansson, G.K., Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med,2005.352(16): p.1685-95.
    3Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell,2004.116(2): p.281-97.
    4miRBase, release14.0. http://microrna.sanger.ac.uk.(September2009).
    5Lu, Y., et al., Transgenic over-expression of the microRNA miR-17-92cluster promotes proliferation and inhibitsdifferentiation of lung epithelial progenitor cells. Dev Biol,2007.310(2): p.442-53.
    6Hwang, H.W. and J.T. Mendell, MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer,2006.94(6): p.776-80.
    7Jovanovic, M. and M.O. Hengartner, miRNAs and apoptosis: RNAs to die for. Oncogene,2006.25(46): p.6176-87.
    8Zhao, Y., E. Samal, and D. Srivastava, Serum response factor regulates a muscle-specific microRNA that targets Hand2during cardiogenesis. Nature,2005.436(7048): p.214-20.
    9Scalbert, E. and A. Bril, Implication of microRNAs in the cardiovascular system. Curr Opin Pharmacol,2008.8(2): p.181-8.
    10Dong, S., et al., MicroRNA expression signature and the role of microRNA-21in the early phase of acute myocardialinfarction. J Biol Chem,2009.284(43): p.29514-25.
    1Blake, G.J. and P.M. Ridker, Novel clinical markers of vascular wall inflammation. Circ Res,2001.89(9): p.763-71.
    2Ji, R., et al., MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA invascular neointimal lesion formation. Circ Res,2007.100(11): p.1579-88.
    3Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell,2004.116(2): p.281-97.
    4Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci US A,2008.105(30): p.10513-8.
    5Chen, T.S., et al., Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res,2010.38(1): p.215-24.
    6Ji, X., et al., Plasma miR-208as a biomarker of myocardial injury. Clin Chem,2009.55(11): p.1944-9.
    7Zernecke, A., et al., Delivery of microRNA-126by apoptotic bodies induces CXCL12-dependent vascular protection.Sci Signal,2009.2(100): p. ra81.
    1D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    2Hoekstra, M., et al., The peripheral blood mononuclear cell microRNA signature of coronary artery disease. BiochemBiophys Res Commun,2010.394(3): p.792-7.
    3Weber, M., et al., MiR-21is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity.Biochem Biophys Res Commun,2010.393(4): p.643-8.
    4Harris, T.A., et al., MicroRNA-126regulates endothelial expression of vascular cell adhesion molecule1. Proc NatlAcad Sci U S A,2008.105(5): p.1516-21.
    5Yoshizaki, K., et al., Conditional expression of microRNA against E-selectin inhibits leukocyte-endothelial adhesiveinteraction under inflammatory condition. Biochem Biophys Res Commun,2008.371(4): p.747-51.
    6Suarez, Y., et al., Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin andintercellular adhesion molecule-1on human endothelial cells: feedback control of inflammation. J Immunol,2010.184(1):p.21-5.
    7Owens, G.K., M.S. Kumar, and B.R. Wamhoff, Molecular regulation of vascular smooth muscle cell differentiation indevelopment and disease. Physiol Rev,2004.84(3): p.767-801.
    8Ji, R., et al., MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA invascular neointimal lesion formation. Circ Res,2007.100(11): p.1579-88.
    9Cheng, Y., et al., MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascularneointimal lesion formation. Circ Res,2009.105(2): p.158-66.
    1Cordes, K.R., et al., miR-145and miR-143regulate smooth muscle cell fate and plasticity. Nature,2009.460(7256): p.705-10.
    2Boettger, T., et al., Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on theMir143/145gene cluster. J Clin Invest,2009.119(9): p.2634-47.
    3Liu, X., et al., A necessary role of miR-221and miR-222in vascular smooth muscle cell proliferation and neointimalhyperplasia. Circ Res,2009.104(4): p.476-87.
    4Davis, B.N., et al., Induction of microRNA-221by platelet-derived growth factor signaling is critical for modulation ofvascular smooth muscle phenotype. J Biol Chem,2009.284(6): p.3728-38.
    5Miyazaki, M. and S. Takai,[Involvement of angiotensin II in development of atherosclerosis]. Nihon Rinsho,2002.60(10): p.1904-10.
    6Zhu, N., et al., Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation andmigration. Atherosclerosis,2011.215(2): p.286-93.
    7Martin, M.M., et al., The human angiotensin II type1receptor+1166A/C polymorphism attenuates microrna-155binding. J Biol Chem,2007.282(33): p.24262-9.
    8Martin, M.M., et al., MicroRNA-155regulates human angiotensin II type1receptor expression in fibroblasts. J BiolChem,2006.281(27): p.18277-84.
    9Pasterkamp, G., J.K. Van Keulen, and D.P. De Kleijn, Role of Toll-like receptor4in the initiation and progression ofatherosclerotic disease. Eur J Clin Invest,2004.34(5): p.328-34.
    1Chen, X.M., et al., A cellular micro-RNA, let-7i, regulates Toll-like receptor4expression and contributes tocholangiocyte immune responses against Cryptosporidium parvum infection. J Biol Chem,2007.282(39): p.28929-38.
    2Liu, G., et al., miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophageinflammatory responses. Proc Natl Acad Sci U S A,2009.106(37): p.15819-24.
    3Shan, Z.X., et al., Upregulated expression of miR-1/miR-206in a rat model of myocardial infarction. BiochemBiophys Res Commun,2009.381(4): p.597-601.
    4Yu, X.Y., et al., Glucose induces apoptosis of cardiomyocytes via microRNA-1and IGF-1. Biochem Biophys ResCommun,2008.376(3): p.548-52.
    5Yin, C., X. Wang, and R.C. Kukreja, Endogenous microRNAs induced by heat-shock reduce myocardial infarctionfollowing ischemia-reperfusion in mice. FEBS Lett,2008.582(30): p.4137-42.
    6Xu, C., et al., The muscle-specific microRNAs miR-1and miR-133produce opposing effects on apoptosis by targetingHSP60, HSP70and caspase-9in cardiomyocytes. J Cell Sci,2007.120(Pt17): p.3045-52.
    7Dong, S., et al., MicroRNA expression signature and the role of microRNA-21in the early phase of acute myocardialinfarction. J Biol Chem,2009.284(43): p.29514-25.
    8Martin, M.M., et al., The human angiotensin II type1receptor+1166A/C polymorphism attenuates microrna-155binding. J Biol Chem,2007.282(33): p.24262-9.
    9O'Connell, R.M., et al., MicroRNA-155is induced during the macrophage inflammatory response. Proc Natl Acad SciU S A,2007.104(5): p.1604-9.
    10O'Connell, R.M., et al., Sustained expression of microRNA-155in hematopoietic stem cells causes amyeloproliferative disorder. J Exp Med,2008.205(3): p.585-94.
    11Rodriguez, A., et al., Requirement of bic/microRNA-155for normal immune function. Science,2007.316(5824): p.608-11.
    12Vigorito, E., et al., microRNA-155regulates the generation of immunoglobulin class-switched plasma cells.2007.27(6): p.847-59.
    13Ceppi, M., et al., MicroRNA-155modulates the interleukin-1signaling pathway in activated humandendritic cells. Proc Natl Acad Sci U S A,2009.106(8): p.2735-40.
    14aganov, K.D., et al., NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signalingproteins of innate immune responses. Proc Natl Acad Sci U S A,2006.103(33): p.12481-6.
    1Chen, T., et al., MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9expression inoxLDL-stimulated monocyte/macrophages. Cardiovasc Res,2009.83(1): p.131-9.
    2Donners, M.M., et al., Hematopoietic miR155deficiency enhances atherosclerosis and decreases plaque stability inhyperlipidemic mice. PLoS One,2012.7(4): p. e35877.
    3Zhu, J., et al., Regulation of microRNA-155in atherosclerotic inflammatory responses by targeting MAP3K10. PLoSOne,2012.7(11): p. e46551.
    4Nazari-Jahantigh, M., et al., MicroRNA-155promotes atherosclerosis by repressing Bcl6in macrophages. J ClinInvest,2012.122(11): p.4190-202.
    5Bonauer, A., et al., MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science,2009.324(5935): p.1710-3.
    6Urbich, C., A. Kuehbacher, and S. Dimmeler, Role of microRNAs in vascular diseases, inflammation, andangiogenesis. Cardiovasc Res,2008.79(4): p.581-8.
    7Bonauer, A., et al., MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science,2009.324(5935): p.1710-3.
    8Kuehbacher, A., C. Urbich, and S. Dimmeler, Targeting microRNA expression to regulate angiogenesis. TrendsPharmacol Sci,2008.29(1): p.12-5.
    9Wang, S. and E.N. Olson, AngiomiRs--key regulators of angiogenesis. Curr Opin Genet Dev,2009.19(3): p.205-11.
    10Kuehbacher, A., et al., Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res,2007.101(1): p.59-68.
    1Fasanaro, P., et al., An integrated approach for experimental target identification of hypoxia-induced miR-210. J BiolChem,2009.284(50): p.35134-43.
    2Tricot, O., et al., Relation between endothelial cell apoptosis and blood flow direction in human atheroscleroticplaques. Circulation,2000.101(21): p.2450-3.
    3Mallat, Z. and A. Tedgui, Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol,2000.130(5): p.947-62.
    4The muscle-specific microRNAs miR-1and miR-133produce opposing effects on apoptosis by targeting HSP60,HSP70and caspase-9in cardiomyocytes. J Cell Sci,2011.124(Pt18): p.3187.
    5Wang, J.X., et al., miR-499regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1.Nat Med,2011.17(1): p.71-8.
    6Wang, X., et al., MicroRNA-494targeting both proapoptotic and antiapoptotic proteins protects againstischemia/reperfusion-induced cardiac injury. Circulation,2010.122(13): p.1308-18.
    7Hu, S., et al., MicroRNA-210as a novel therapy for treatment of ischemic heart disease. Circulation,2010.122(11Suppl): p. S124-31.
    8Zhu, G.F., et al., miR-155inhibits oxidized low-density lipoprotein-induced apoptosis of RAW264.7cells. Mol CellBiochem,2013.
    9Gironella, M., et al., Tumor protein53-induced nuclear protein1expression is repressed by miR-155, and itsrestoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A,2007.104(41): p.16170-5.
    10Meng, W., et al., Anti-miR-155oligonucleotide enhances chemosensitivity of U251cell to taxol by inducingCell Biol Int,2012.
    1Zheng, S.R., et al., Clinical significance of miR-155expression in breast cancer and effects of miR-155ASO on cellviability and apoptosis. Oncol Rep,2012.27(4): p.1149-55.
    2Kim, J.H., W.S. Kim, and C. Park, Epstein-Barr virus latent membrane protein-1protects B-cell lymphoma fromrituximab-induced apoptosis through miR-155-mediated Akt activation and up-regulation of Mcl-1. Leuk Lymphoma,2012.
    3Ovcharenko, D., et al., Genome-scale microRNA and small interfering RNA screens identify small RNA modulators ofTRAIL-induced apoptosis pathway. Cancer Res,2007.67(22): p.10782-8.
    4Pottier, N., et al., Identification of keratinocyte growth factor as a target of microRNA-155in lung fibroblasts:implication in epithelial-mesenchymal interactions. PLoS One,2009.4(8): p. e6718.
    5Lu, C., et al., miR-221and miR-155regulate human dendritic cell development, apoptosis, and IL-12productionthrough targeting of p27kip1, KPC1, and SOCS-1. Blood,2011.117(16): p.4293-303.
    6Esau, C., et al., miR-122regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab,2006.3(2):p.87-98.
    7Nakanishi, N., et al., The up-regulation of microRNA-335is associated with lipid metabolism in liver and whiteadipose tissue of genetically obese mice. Biochem Biophys Res Commun,2009.385(4): p.492-6.
    8Poy, M.N., et al., A pancreatic islet-specific microRNA regulates insulin secretion. Nature,2004.432(7014): p.226-30.
    9Rayner, K.J., et al., Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides.Nature,2011.478(7369): p.404-7.
    1Marquart, T.J., et al., Anti-miR-33therapy does not alter the progression of atherosclerosis in low-density lipoproteinreceptor-deficient mice. Arterioscler Thromb Vasc Biol,2013.33(3): p.455-8.
    2van Rooij, E., W.S. Marshall, and E.N. Olson, Toward microRNA-based therapeutics for heart disease: the sense inantisense. Circ Res,2008.103(9): p.919-28.
    3Silvestri, P., et al., MicroRNAs and ischemic heart disease: towards a better comprehension of pathogenesis, newdiagnostic tools and new therapeutic targets. Recent Pat Cardiovasc Drug Discov,2009.4(2): p.109-18.
    1Krutzfeldt, J., et al., Silencing of microRNAs in vivo with 'antagomirs'. Nature,2005.438(7068): p.685-9.
    2Esau, C., et al., miR-122regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab,2006.3(2):p.87-98.
    3Lanford, R.E., et al., Therapeutic silencing of microRNA-122in primates with chronic hepatitis C virus infection.Science,2010.327(5962): p.198-201.
    4Cheng, Y., et al., MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascularneointimal lesion formation. Circ Res,2009.105(2): p.158-66.
    5Boettger, T., et al., Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on theMir143/145gene cluster. J Clin Invest,2009.119(9): p.2634-47.
    6Ji, R., et al., MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA invascular neointimal lesion formation. Circ Res,2007.100(11): p.1579-88.
    1. Pieper, K.S., et al., Validity of a risk-prediction tool for hospital mortality: the GlobalRegistry of Acute Coronary Events. Am Heart J,2009.157(6): p.1097-105.
    2. Falk, E., P.K. Shah, and V. Fuster, Coronary plaque disruption. Circulation,1995.92(3): p.657-71.
    3. Glaser, R., et al., Clinical progression of incidental, asymptomatic lesions discoveredduring culprit vessel coronary intervention. Circulation,2005.111(2): p.143-9.
    4. Schaar, J.A., et al., Terminology for high-risk and vulnerable coronary artery plaques.Report of a meeting on the vulnerable plaque, June17and18,2003, Santorini, Greece.Eur Heart J,2004.25(12): p.1077-82.
    5. Virmani, R., et al., Pathology of the vulnerable plaque. J Am Coll Cardiol,2006.47(8Suppl): p. C13-8.
    6. Lee, R.C., R.L. Feinbaum, and V. Ambros, The C. elegans heterochronic gene lin-4encodes small RNAs with antisense complementarity to lin-14. Cell,1993.75(5): p.843-54.
    7. Novina, C.D. and P.A. Sharp, The RNAi revolution. Nature,2004.430(6996): p.161-4.
    8. Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell,2004.116(2): p.281-97.
    9. Hwang, H.W. and J.T. Mendell, MicroRNAs in cell proliferation, cell death, andtumorigenesis. Br J Cancer,2006.94(6): p.776-80.
    10. Jovanovic, M. and M.O. Hengartner, miRNAs and apoptosis: RNAs to die for.Oncogene,2006.25(46): p.6176-87.
    11. Lu, Y., et al., Transgenic over-expression of the microRNA miR-17-92cluster promotesproliferation and inhibits differentiation of lung epithelial progenitor cells. Dev Biol,2007.310(2): p.442-53.
    12. Zhao, Y., E. Samal, and D. Srivastava, Serum response factor regulates amuscle-specific microRNA that targets Hand2during cardiogenesis. Nature,2005.436(7048): p.214-20.
    13. Ji, R., et al., MicroRNA expression signature and antisense-mediated depletion revealan essential role of MicroRNA in vascular neointimal lesion formation. Circ Res,2007.100(11): p.1579-88.
    14. Care, A., et al., MicroRNA-133controls cardiac hypertrophy. Nat Med,2007.13(5): p.613-8.
    15. Yang, B., et al., The muscle-specific microRNA miR-1regulates cardiacarrhythmogenic potential by targeting GJA1and KCNJ2. Nat Med,2007.13(4): p.486-91.
    16. van Rooij, E., et al., Dysregulation of microRNAs after myocardial infarction reveals arole of miR-29in cardiac fibrosis. Proc Natl Acad Sci U S A,2008.105(35): p.13027-32.
    17. Narula, J., et al., Mechanisms of disease: apoptosis in heart failure--seeing hope indeath. Nat Clin Pract Cardiovasc Med,2006.3(12): p.681-8.
    18. Chen, T., et al., MicroRNA-125a-5p partly regulates the inflammatory response, lipiduptake, and ORP9expression in oxLDL-stimulated monocyte/macrophages.Cardiovasc Res,2009.83(1): p.131-9.
    19. Tam, W. and J.E. Dahlberg, miR-155/BIC as an oncogenic microRNA. GenesChromosomes Cancer,2006.45(2): p.211-2.
    20. Georgantas, R.W.,3rd, et al., CD34+hematopoietic stem-progenitor cell microRNAexpression and function: a circuit diagram of differentiation control. Proc Natl AcadSci U S A,2007.104(8): p.2750-5.
    21. Rodriguez, A., et al., Requirement of bic/microRNA-155for normal immune function.Science,2007.316(5824): p.608-11.
    22. Thai, T.H., et al., Regulation of the germinal center response by microRNA-155.Science,2007.316(5824): p.604-8.
    23. Martin, S.E. and N.J. Caplen, Applications of RNA interference in mammalian systems.Annu Rev Genomics Hum Genet,2007.8: p.81-108.
    24. Taganov, K.D., et al., NF-kappaB-dependent induction of microRNA miR-146, aninhibitor targeted to signaling proteins of innate immune responses. Proc Natl AcadSci U S A,2006.103(33): p.12481-6.
    25. Zhu, N., et al., Endothelial enriched microRNAs regulate angiotensin II-inducedendothelial inflammation and migration. Atherosclerosis,2011.215(2): p.286-93.
    26. Martin, M.M., et al., The human angiotensin II type1receptor+1166A/Cpolymorphism attenuates microrna-155binding. J Biol Chem,2007.282(33): p.24262-9.
    27. Martin, M.M., et al., MicroRNA-155regulates human angiotensin II type1receptorexpression in fibroblasts. J Biol Chem,2006.281(27): p.18277-84.
    28. O'Connell, R.M., et al., MicroRNA-155is induced during the macrophageinflammatory response. Proc Natl Acad Sci U S A,2007.104(5): p.1604-9.
    29. Ruggiero, T., et al., LPS induces KH-type splicing regulatory protein-dependentprocessing of microRNA-155precursors in macrophages. FASEB J,2009.23(9): p.2898-908.
    30. Tang, B., et al., Identification of MyD88as a novel target of miR-155, involved innegative regulation of Helicobacter pylori-induced inflammation. FEBS Lett,2010.584(8): p.1481-6.
    31. He, M., et al., MicroRNA-155regulates inflammatory cytokine production intumor-associated macrophages via targeting C/EBPbeta. Cell Mol Immunol,2009.6(5): p.343-52.
    32. Xiao, B., et al., Induction of microRNA-155during Helicobacter pylori infection andits negative regulatory role in the inflammatory response. J Infect Dis,2009.200(6): p.916-25.
    33. Huang, R.S., et al., MicroRNA-155Silencing Enhances Inflammatory Response andLipid Uptake in Oxidized Low-Density Lipoprotein-Stimulated Human THP-1Macrophages. J Investig Med,2010.58(8): p.961-7.
    34. Rossi, M.L., et al., Different quantitative apoptotic traits in coronary atheroscleroticplaques from patients with stable angina pectoris and acute coronary syndromes.Circulation,2004.110(13): p.1767-73.
    35. Littlewood, T.D. and M.R. Bennett, Apoptotic cell death in atherosclerosis. Curr OpinLipidol,2003.14(5): p.469-75.
    36. Tabas, I., Apoptosis and plaque destabilization in atherosclerosis: the role ofmacrophage apoptosis induced by cholesterol. Cell Death Differ,2004.11Suppl1: p.S12-6.
    37. Schrijvers, D.M., et al., Phagocytosis in atherosclerosis: Molecular mechanisms andimplications for plaque progression and stability. Cardiovasc Res,2007.73(3): p.470-80.
    38. Yla-Herttuala, S., et al., Evidence for the presence of oxidatively modified low densitylipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest,1989.84(4): p.1086-95.
    39. Colles, S.M., et al., Oxidized LDL-induced injury and apoptosis in atherosclerosis.Potential roles for oxysterols. Trends Cardiovasc Med,2001.11(3-4): p.131-8.
    40. Salvayre, R., et al., Oxidized low-density lipoprotein-induced apoptosis. BiochimBiophys Acta,2002.1585(2-3): p.213-21.
    41. Napoli, C., Oxidation of LDL, atherogenesis, and apoptosis. Ann N Y Acad Sci,2003.1010: p.698-709.
    42. Sata, M. and K. Walsh, Oxidized LDL activates fas-mediated endothelial cell apoptosis.J Clin Invest,1998.102(9): p.1682-9.
    43. Chen, J., et al., Role of caspases in Ox-LDL-induced apoptotic cascade in humancoronary artery endothelial cells. Circ Res,2004.94(3): p.370-6.
    44. Li, H.L., et al., A20inhibits oxidized low-density lipoprotein-induced apoptosisthrough negative Fas/Fas ligand-dependent activation of caspase-8and mitochondrialpathways in murine RAW264.7macrophages. J Cell Physiol,2006.208(2): p.307-18.
    45. Wang, H.Q., et al., Deregulated miR-155promotes Fas-mediated apoptosis in humanintervertebral disc degeneration by targeting FADD and caspase-3. J Pathol,2011.
    46. Tili, E., et al., Modulation of miR-155and miR-125b levels followinglipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating theresponse to endotoxin shock. J Immunol,2007.179(8): p.5082-9.
    47. Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancerdetection. Proc Natl Acad Sci U S A,2008.105(30): p.10513-8.
    48. Skog, J., et al., Glioblastoma microvesicles transport RNA and proteins that promotetumour growth and provide diagnostic biomarkers. Nat Cell Biol,2008.10(12): p.1470-6.
    49. Shan, Z.X., et al., Upregulated expression of miR-1/miR-206in a rat model ofmyocardial infarction. Biochem Biophys Res Commun,2009.381(4): p.597-601.
    50. D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers ofmyocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    51. Fichtlscherer, S., et al., Circulating microRNAs in patients with coronary arterydisease. Circ Res,2010.107(5): p.677-84.
    52. Yao, R., et al., The altered expression of inflammation-related microRNAs withmicroRNA-155expression correlates with Th17differentiation in patients with acutecoronary syndrome. Cell Mol Immunol,2011.8(6): p.486-95.
    53. Hedin, U., J. Roy, and P.K. Tran, Control of smooth muscle cell proliferation invascular disease. Curr Opin Lipidol,2004.15(5): p.559-65.
    54. Zhu, J., et al., Regulation of microRNA-155in atherosclerotic inflammatory responsesby targeting MAP3K10. PLoS One,2012.7(11): p. e46551.
    55. Donners, M.M., et al., Hematopoietic miR155deficiency enhances atherosclerosis anddecreases plaque stability in hyperlipidemic mice. PLoS One,2012.7(4): p. e35877.
    56. Gensini, G.G., A more meaningful scoring system for determining the severity ofcoronary heart disease. Am J Cardiol,1983.51(3): p.606.
    57. Stahl, H.F., et al., miR-155inhibition sensitizes CD4+Th cells for TREG mediatedsuppression. PLoS One,2009.4(9): p. e7158.
    58. Banerjee, A., et al., Micro-RNA-155inhibits IFN-gamma signaling in CD4+T cells.Eur J Immunol,2010.40(1): p.225-31.
    59. Lu, L.F., et al., Foxp3-dependent microRNA155confers competitive fitness toregulatory T cells by targeting SOCS1protein. Immunity,2009.30(1): p.80-91.
    60. Pottier, N., et al., Identification of keratinocyte growth factor as a target ofmicroRNA-155in lung fibroblasts: implication in epithelial-mesenchymal interactions.PLoS One,2009.4(8): p. e6718.
    61. Chen, T., et al., MicroRNA-155regulates lipid uptake, adhesion/chemokine markersecretion and SCG2expression in oxLDL-stimulated dendritic cells/macrophages. Int JCardiol,2011.147(3): p.446-7.
    62. Hoekstra, M., et al., The peripheral blood mononuclear cell microRNA signature ofcoronary artery disease. Biochem Biophys Res Commun,2010.394(3): p.792-7.
    63. Nazari-Jahantigh, M., et al., MicroRNA-155promotes atherosclerosis by repressingBcl6in macrophages. J Clin Invest,2012.122(11): p.4190-202.
    64. Gilad, S., et al., Serum microRNAs are promising novel biomarkers. PLoS One,2008.3(9): p. e3148.
    65. Wang, L.G. and J. Gu, Serum microRNA-29a is a promising novel marker for earlydetection of colorectal liver metastasis. Cancer Epidemiol,2011.
    66. Fang, C., et al., Serum microRNAs are promising novel biomarkers for diffuse large Bcell lymphoma. Ann Hematol,2011.
    67. Burgess, D.J., Glioblastoma: Microvesicles as major biomarkers? Nat Rev Cancer,2013.13(1): p.8.
    68. Hunter, M.P., et al., Detection of microRNA expression in human peripheral bloodmicrovesicles. PLoS One,2008.3(11): p. e3694.
    69. Zernecke, A., et al., Delivery of microRNA-126by apoptotic bodies inducesCXCL12-dependent vascular protection. Sci Signal,2009.2(100): p. ra81.
    70. Wang K, Z.S., Weber J, Baxter D, Galas DJ, Mammalian cells in culture activelyexport specific microRNAs. Nature Precedings,2009.
    71. Deregibus, M.C., et al., Endothelial progenitor cell derived microvesicles activate anangiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood,2007.110(7): p.2440-8.
    72. Ai, J., et al., Circulating microRNA-1as a potential novel biomarker for acutemyocardial infarction. Biochem Biophys Res Commun,2010.391(1): p.73-7.
    73. Wang, G.K., et al., Circulating microRNA: a novel potential biomarker for earlydiagnosis of acute myocardial infarction in humans. Eur Heart J,2010.31(6): p.659-66.
    74. Horne, B.D., et al., Statin therapy, lipid levels, C-reactive protein and the survival ofpatients with angiographically severe coronary artery disease. J Am Coll Cardiol,2000.36(6): p.1774-80.
    75. Norja, S., et al., C-reactive protein in vulnerable coronary plaques. J Clin Pathol,2007.60(5): p.545-8.
    76. Sabatine, M.S., et al., Prognostic significance of the Centers for DiseaseControl/American Heart Association high-sensitivity C-reactive protein cut points forcardiovascular and other outcomes in patients with stable coronary artery disease.Circulation,2007.115(12): p.1528-36.
    77. Newby, A.C., Dual role of matrix metalloproteinases (matrixins) in intimal thickeningand atherosclerotic plaque rupture. Physiol Rev,2005.85(1): p.1-31.
    78. Boyle, J.J., P.L. Weissberg, and M.R. Bennett, Human macrophage-induced vascularsmooth muscle cell apoptosis requires NO enhancement of Fas/Fas-L interactions.Arterioscler Thromb Vasc Biol,2002.22(10): p.1624-30.
    79. Gautier, E.L., et al., Macrophage apoptosis exerts divergent effects on atherogenesis asa function of lesion stage. Circulation,2009.119(13): p.1795-804.
    80. Guo, R.W., et al., Stim1-and Orai1-mediated store-operated calcium entry is criticalfor angiotensin II-induced vascular smooth muscle cell proliferation. Cardiovasc Res,2011.
    81. Yang, L.X., et al.,[Association between murine double minute2expression and AngIIand ceramide induced endothelial cells apoptosis]. Zhonghua Xin Xue Guan Bing ZaZhi,2007.35(10): p.945-8.
    82. Yang, L.X., et al., Angiotensin II induces extracellular matrix metalloproteinaseinducer expression via an AT1R dependent pathway in aortic atherosclerotic plaque inapolipoprotein E knockout mice. J Renin Angiotensin Aldosterone Syst,2011.
    83. Yang, L.X., et al., The effect of the expression of angiotensin II on extracellular matrixmetalloproteinase inducer (EMMPRIN) in macrophages is mediated via theAT1/COX-2/PGE2pathway. Inflamm Res,2010.59(12): p.1033-40.
    84. Guo, R.W., et al., Angiotensin II induces NF-kappa B activation in HUVEC via thep38MAPK pathway. Peptides,2006.27(12): p.3269-75.
    85. Gironella, M., et al., Tumor protein53-induced nuclear protein1expression isrepressed by miR-155, and its restoration inhibits pancreatic tumor development. ProcNatl Acad Sci U S A,2007.104(41): p.16170-5.
    86. Ovcharenko, D., et al., Genome-scale microRNA and small interfering RNA screensidentify small RNA modulators of TRAIL-induced apoptosis pathway. Cancer Res,2007.67(22): p.10782-8.
    87. Boullier, A., et al., Minimally oxidized LDL offsets the apoptotic effects of extensivelyoxidized LDL and free cholesterol in macrophages. Arterioscler Thromb Vasc Biol,2006.26(5): p.1169-76.
    88. Tricot, O., et al., Relation between endothelial cell apoptosis and blood flow directionin human atherosclerotic plaques. Circulation,2000.101(21): p.2450-3.
    89. Mallat, Z. and A. Tedgui, Apoptosis in the vasculature: mechanisms and functionalimportance. Br J Pharmacol,2000.130(5): p.947-62.
    90. Liu, J., et al., Reduced macrophage apoptosis is associated with acceleratedatherosclerosis in low-density lipoprotein receptor-null mice. Arterioscler ThrombVasc Biol,2005.25(1): p.174-9.
    91. van Reyk, D.M., W. Jessup, and R.T. Dean, Prooxidant and antioxidant activities ofmacrophages in metal-mediated LDL oxidation: the importance of metal sequestration.Arterioscler Thromb Vasc Biol,1999.19(4): p.1119-24.
    92. Baoutina, A., R.T. Dean, and W. Jessup, Macrophages can decrease the level ofcholesteryl ester hydroperoxides in low density lipoprotein. J Biol Chem,2000.275(3):p.1635-44.
    93. Bjorkerud, S. and B. Bjorkerud, Apoptosis is abundant in human atheroscleroticlesions, especially in inflammatory cells (macrophages and T cells), and maycontribute to the accumulation of gruel and plaque instability. Am J Pathol,1996.149(2): p.367-80.
    94. Tabas, I., Consequences and therapeutic implications of macrophage apoptosis inatherosclerosis: the importance of lesion stage and phagocytic efficiency. ArteriosclerThromb Vasc Biol,2005.25(11): p.2255-64.
    95. Kolodgie, F.D., et al., Localization of apoptotic macrophages at the site of plaquerupture in sudden coronary death. Am J Pathol,2000.157(4): p.1259-68.
    96. Libby, P., et al., Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol,1996.7(5): p.330-5.
    97. Kockx, M.M. and A.G. Herman, Apoptosis in atherosclerosis: beneficial ordetrimental? Cardiovasc Res,2000.45(3): p.736-46.
    98. van Vlijmen, B.J., et al., Macrophage p53deficiency leads to enhanced atherosclerosisin APOE*3-Leiden transgenic mice. Circ Res,2001.88(8): p.780-6.
    99. Hutter, R., et al., Caspase-3and tissue factor expression in lipid-rich plaquemacrophages: evidence for apoptosis as link between inflammation andatherothrombosis. Circulation,2004.109(16): p.2001-8.
    100. Jovinge, S., et al., Human monocytes/macrophages release TNF-alpha in response toOx-LDL. Arterioscler Thromb Vasc Biol,1996.16(12): p.1573-9.
    101. Kinscherf, R., et al., Modified low density lipoprotein delivers substrate for ceramideformation and stimulates the sphingomyelin-ceramide pathway in human macrophages.FEBS Lett,1997.405(1): p.55-9.
    102. Kinscherf, R., et al., Induction of mitochondrial manganese superoxide dismutase inmacrophages by oxidized LDL: its relevance in atherosclerosis of humans andheritable hyperlipidemic rabbits. FASEB J,1997.11(14): p.1317-28.
    103. Kinscherf, R., et al., Apoptosis caused by oxidized LDL is manganese superoxidedismutase and p53dependent. FASEB J,1998.12(6): p.461-7.
    104. Kinscherf, R., et al., Characterization of apoptotic macrophages in atheromatoustissue of humans and heritable hyperlipidemic rabbits. Atherosclerosis,1999.144(1):p.33-9.
    105. Deigner, H.P., et al., Ceramide induces aSMase expression: implications foroxLDL-induced apoptosis. FASEB J,2001.15(3): p.807-14.
    106. Hardwick, S.J., et al., Apoptosis in human monocyte-macrophages exposed to oxidizedlow density lipoprotein. J Pathol,1996.179(3): p.294-302.
    107. He, L. and G.J. Hannon, MicroRNAs: small RNAs with a big role in gene regulation.Nat Rev Genet,2004.5(7): p.522-31.
    108. Alvarez-Garcia, I. and E.A. Miska, MicroRNA functions in animal development andhuman disease. Development,2005.132(21): p.4653-62.
    109. Wei, Y., et al., The microRNA-342-5p Fosters Inflammatory Macrophage ActivationThrough an Akt1-and microRNA-155-Dependent Pathway During Atherosclerosis.Circulation,2013.127(15): p.1609-19.
    110. Meng, W., et al., Anti-miR-155oligonucleotide enhances chemosensitivity of U251cellto taxol by inducing apoptosis. Cell Biol Int,2012.
    111. Zheng, S.R., et al., Clinical significance of miR-155expression in breast cancer andeffects of miR-155ASO on cell viability and apoptosis. Oncol Rep,2012.27(4): p.1149-55.
    112. Kim, J.H., W.S. Kim, and C. Park, Epstein-Barr virus latent membrane protein-1protects B-cell lymphoma from rituximab-induced apoptosis throughmiR-155-mediated Akt activation and up-regulation of Mcl-1. Leuk Lymphoma,2012.
    113. Lu, C., et al., miR-221and miR-155regulate human dendritic cell development,apoptosis, and IL-12production through targeting of p27kip1, KPC1, and SOCS-1.Blood,2011.117(16): p.4293-303.
    114. Zadelaar, A.S., et al., Increased vulnerability of pre-existing atherosclerosis inApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer.Atherosclerosis,2005.183(2): p.244-50.
    115. Nhan, T.Q., et al., The p17cleaved form of caspase-3is present within viablemacrophages in vitro and in atherosclerotic plaque. Arterioscler Thromb Vasc Biol,2003.23(7): p.1276-82.
    116. Ermak, N., et al., Role of reactive oxygen species and Bax in oxidized low densitylipoprotein-induced apoptosis of human monocytes. Atherosclerosis,2008.200(2): p.247-56.
    117. Zhang, Y., et al., Conditional Fas-associated death domain protein (FADD): GFPknockout mice reveal FADD is dispensable in thymic development but essential inperipheral T cell homeostasis. J Immunol,2005.175(5): p.3033-44.
    1. Ho, J.S., et al., Utility of high-sensitivity C-reactive protein versus coronary arterycalcium for the detection of obstructive stenoses in stable patients. Am J Cardiol,2013.111(3): p.328-32.
    2. Koenig, W., High-sensitivity C-reactive protein and atherosclerotic disease: Fromimproved risk prediction to risk-guided therapy. Int J Cardiol,2013.
    3. Seo, S.M., et al., Correlations between the level of high-sensitivity c-reactive proteinand cardiovascular risk factors in korean adults with cardiovascular disease ordiabetes mellitus: the CALLISTO study. J Atheroscler Thromb,2013.20(7): p.616-22.
    4. Whelton, S.P., et al., Elevated High-Sensitivity C-Reactive Protein as a Risk Marker ofthe Attenuated Relationship Between Serum Cholesterol and Cardiovascular Events atOlder Age: The ARIC Study. Am J Epidemiol,2013.178(7): p.1076-84.
    5. Rus, H. and F.I. Niculescu, Inflammation, aspirin, and the risk of cardiovasculardisease. N Engl J Med,1997.337(6): p.423; author reply423-4.
    6. Berk, B.C., W.S. Weintraub, and R.W. Alexander, Elevation of C-reactive protein in"active" coronary artery disease. Am J Cardiol,1990.65(3): p.168-72.
    7.何松清,江.,血清MMP-2、CRP水平对不稳定性心绞痛的诊断及预后判断价值.医学研究生学报,2001.14(4): p.316-8
    8.曹相誉,杨.,李会利,血清C反应蛋白对不稳定型心绞痛近期预后的评价.疑难病杂志,20032(3): p.136-8
    9.中华医学会心血管病学分会,全国心绞痛及心肌缺血学术研讨会纪要.中华心血管病杂志,200028(6): p.405-8.
    10.王振义,李.,阮长耿,等,血栓与止血-基础理论与临床. M2版.上海:上海科学技术出版社,1996.:382.
    11.张莉,卢.,王毅,等,冠心病85例血浆纤维蛋白原、D-二聚体含量检测的临床价值.南通大学学报(医学版),200525(2): p.116.
    12.徐辉,蔡.,夏明凯,等,冠心病患者血D2二聚体和血栓前体蛋白含量变化及其临床意义.新医学,200536(3): p.147.
    13.杨颉,宫.,心绞痛和脑血栓病人止血与凝血分子标志物的检测.青岛大学医学院学报,,2001.37(4): p.337-8.
    14.崔家玉,高.,王丽萍,等.,不稳定心绞痛血凝/纤溶系统变化临床研究.实用心脑肺血管病杂志,2003.11(1): p.8-11
    15.田华,尚.,房桂青.,肌钙蛋白T、C反应蛋白、D-二聚体在判定不稳定型心绞痛预后中的价值.山东医药,2004.44(14): p.15-6.
    16. Pirillo, A., G.D. Norata, and A.L. Catapano, Treating high density lipoproteincholesterol (HDL-C): quantity versus quality. Curr Pharm Des,2013.19(21): p.3841-57.
    17. Young, C.E., R.H. Karas, and J.T. Kuvin, High-density lipoprotein cholesterol andcoronary heart disease. Cardiol Rev,2004.12(2): p.107-19.
    18. Castelli, W.P., et al., Incidence of coronary heart disease and lipoprotein cholesterollevels. The Framingham Study. JAMA,1986.256(20): p.2835-8.
    19. Kitamura, A., et al., Association between non-high-density lipoprotein cholesterollevels and the incidence of coronary heart disease among Japanese: the CirculatoryRisk in Communities Study (CIRCS). J Atheroscler Thromb,2011.18(6): p.454-63.
    20. Sacks, F.M., The role of high-density lipoprotein (HDL) cholesterol in the preventionand treatment of coronary heart disease: expert group recommendations. Am J Cardiol,2002.90(2): p.139-43.
    21. Rus, H. and F. Niculescu, Inflammatory response in unstable angina. Circulation,1999.100(19): p. e98.
    22. Harb, T.S., et al., Association of C-reactive protein and serum amyloid A with recurrentcoronary events in stable patients after healing of acute myocardial infarction. Am JCardiol,2002.89(2): p.216-21.
    23. Ridker, P.M., et al., C-reactive protein and other markers of inflammation in theprediction of cardiovascular disease in women. N Engl J Med,2000.342(12): p.836-43.
    24.李成乾,于.,不稳定型心绞痛病人血清IL-6检测及其意义.齐鲁医学杂志,2001.16(3): p.198-9
    25.白璐,罗.,胡成进,等, TNF-α、IL-8与老年急性冠状动脉综合征关系的研究.放射免疫学杂志,2005.18(4): p.246.
    26. Cui, Y., et al., Circulating microparticles in patients with coronary heart disease andits correlation with interleukin-6and C-reactive protein. Mol Biol Rep,2013.
    27. Kanda, T., et al., Interleukin-8as a sensitive marker of unstable coronary arterydisease. Am J Cardiol,1996.77(4): p.304-7.
    28. Olivotti, L., et al., Maximal endothelial tissue plasminogen activator release is notimpaired in patients with acute coronary syndromes before heparin treatment. BloodCoagul Fibrinolysis,2001.12(4): p.261-7.
    29.吕克,刘.,蒋绮年,不稳定性心绞痛患者血浆组织型纤溶酶原激活物含量变化及其在危险分层中的意义.苏州大学学报(医学版),200424(6): p.896.
    30. Jansson, J.H., B.O. Olofsson, and T.K. Nilsson, Predictive value of tissue plasminogenactivator mass concentration on long-term mortality in patients with coronary arterydisease. A7-year follow-up. Circulation,1993.88(5Pt1): p.2030-4.
    31. Thompson, S.G., et al., Hemostatic factors and the risk of myocardial infarction orsudden death in patients with angina pectoris. European Concerted Action onThrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med,1995.332(10): p.635-41.
    32. Ridker, P.M., et al., Endogenous tissue-type plasminogen activator and risk ofmyocardial infarction. Lancet,1993.341(8854): p.1165-8.
    33. Ekmekci, H., et al., Significance of vitronectin and PAI-1activity levels in carotidartery disease: comparison of symptomatic and asymptomatic patients. Minerva Med,2013.104(2): p.215-23.
    34.马娜,张.,魏宏顺,等,冠心病血清胆红素浓度与cTnT、血栓素A2关系的研究.临床心血管病杂志,2004.20(10): p.627.
    35. Defilippis, A.P., et al., Thromboxane A Generation, in the Absence of Platelet COX-1Activity, in Patients With and Without Atherothrombotic Myocardial Infarction. Circ J,2013.
    36. Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancerdetection. Proc Natl Acad Sci U S A,2008.105(30): p.10513-8.
    37. Skog, J., et al., Glioblastoma microvesicles transport RNA and proteins that promotetumour growth and provide diagnostic biomarkers. Nat Cell Biol,2008.10(12): p.1470-6.
    38. D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers ofmyocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    39. Hoekstra, M., et al., The peripheral blood mononuclear cell microRNA signature ofcoronary artery disease. Biochem Biophys Res Commun,2010.394(3): p.792-7.
    40. Ji, X., et al., Plasma miR-208as a biomarker of myocardial injury. Clin Chem,2009.55(11): p.1944-9.
    41. Ai, J., et al., Circulating microRNA-1as a potential novel biomarker for acutemyocardial infarction. Biochem Biophys Res Commun,2010.391(1): p.73-7.
    42. Fichtlscherer, S., et al., Circulating microRNAs in patients with coronary artery disease.Circ Res,2010.107(5): p.677-84.
    43. De Rosa, S., et al., Transcoronary concentration gradients of circulating microRNAs.Circulation,2011.124(18): p.1936-44.
    44.张俊峰等,细胞外基质金属蛋白酶诱导因子与冠心病临床类型的关系.上海交通大学学报(医学版),2009.12-1431-03
    45. Kaden, J.J., et al., Time-dependent changes in the plasma concentration of matrixmetalloproteinase9after acute myocardial infarction. Cardiology,2003.99(3): p.140-4.
    46. Hayashidani, S., et al., Targeted deletion of MMP-2attenuates early LV rupture andlate remodeling after experimental myocardial infarction. Am J Physiol Heart CircPhysiol,2003.285(3): p. H1229-35.
    47. Brehm, B.R., et al., Comparison of circulating endothelin-1and big endothelin-1levelsin unstable versus stable angina pectoris. J Cardiovasc Pharmacol,1998.31Suppl1: p.S90-3.
    48. Kimmel, M., et al., Improved estimation of glomerular filtration rate by serum cystatinC in preventing contrast induced nephropathy by N-acetylcysteine or zinc--preliminaryresults. Nephrol Dial Transplant,2008.23(4): p.1241-5.
    49. Omland, T., et al., Circulating osteoprotegerin levels and long-term prognosis inpatients with acute coronary syndromes. J Am Coll Cardiol,2008.51(6): p.627-33.
    1. Ross, R., Atherosclerosis--an inflammatory disease. N Engl J Med,1999.340(2): p.115-26.
    2. Hansson, G.K., Inflammation, atherosclerosis, and coronary artery disease. N Engl JMed,2005.352(16): p.1685-95.
    3. Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell,2004.116(2): p.281-97.
    4. miRBase, release14.0. http://microrna.sanger.ac.uk.(September2009).
    5. Hwang, H.W. and J.T. Mendell, MicroRNAs in cell proliferation, cell death, andtumorigenesis. Br J Cancer,2006.94(6): p.776-80.
    6. Jovanovic, M. and M.O. Hengartner, miRNAs and apoptosis: RNAs to die for. Oncogene,2006.25(46): p.6176-87.
    7. Lu, Y., et al., Transgenic over-expression of the microRNA miR-17-92cluster promotesproliferation and inhibits differentiation of lung epithelial progenitor cells. Dev Biol,2007.310(2): p.442-53.
    8. Zhao, Y., E. Samal, and D. Srivastava, Serum response factor regulates amuscle-specific microRNA that targets Hand2during cardiogenesis. Nature,2005.436(7048): p.214-20.
    9. Blake, G.J. and P.M. Ridker, Novel clinical markers of vascular wall inflammation. CircRes,2001.89(9): p.763-71.
    10. Dong, S., et al., MicroRNA expression signature and the role of microRNA-21in theearly phase of acute myocardial infarction. J Biol Chem,2009.284(43): p.29514-25.
    11. Ji, R., et al., MicroRNA expression signature and antisense-mediated depletion revealan essential role of MicroRNA in vascular neointimal lesion formation. Circ Res,2007.100(11): p.1579-88.
    12. Scalbert, E. and A. Bril, Implication of microRNAs in the cardiovascular system. CurrOpin Pharmacol,2008.8(2): p.181-8.
    13. Zhang, C., MicroRNA and vascular smooth muscle cell phenotype: new therapy foratherosclerosis? Genome Med,2009.1(9): p.85.
    14. Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancerdetection. Proc Natl Acad Sci U S A,2008.105(30): p.10513-8.
    15. Skog, J., et al., Glioblastoma microvesicles transport RNA and proteins that promotetumour growth and provide diagnostic biomarkers. Nat Cell Biol,2008.10(12): p.1470-6.
    16. Valadi, H., et al., Exosome-mediated transfer of mRNAs and microRNAs is a novelmechanism of genetic exchange between cells. Nat Cell Biol,2007.9(6): p.654-9.
    17. Chen, T.S., et al., Mesenchymal stem cell secretes microparticles enriched inpre-microRNAs. Nucleic Acids Res,2010.38(1): p.215-24.
    18. Ji, X., et al., Plasma miR-208as a biomarker of myocardial injury. Clin Chem,2009.55(11): p.1944-9.
    19. Zernecke, A., et al., Delivery of microRNA-126by apoptotic bodies inducesCXCL12-dependent vascular protection. Sci Signal,2009.2(100): p. ra81.
    20. D'Alessandra, Y., et al., Circulating microRNAs are new and sensitive biomarkers ofmyocardial infarction. Eur Heart J,2010.31(22): p.2765-73.
    21. Hoekstra, M., et al., The peripheral blood mononuclear cell microRNA signature ofcoronary artery disease. Biochem Biophys Res Commun,2010.394(3): p.792-7.
    22. Weber, M., et al., MiR-21is induced in endothelial cells by shear stress and modulatesapoptosis and eNOS activity. Biochem Biophys Res Commun,2010.393(4): p.643-8.
    23. Harris, T.A., et al., MicroRNA-126regulates endothelial expression of vascular celladhesion molecule1. Proc Natl Acad Sci U S A,2008.105(5): p.1516-21.
    24. Yoshizaki, K., et al., Conditional expression of microRNA against E-selectin inhibitsleukocyte-endothelial adhesive interaction under inflammatory condition. BiochemBiophys Res Commun,2008.371(4): p.747-51.
    25. Suarez, Y., et al., Cutting edge: TNF-induced microRNAs regulate TNF-inducedexpression of E-selectin and intercellular adhesion molecule-1on human endothelialcells: feedback control of inflammation. J Immunol,2010.184(1): p.21-5.
    26. Owens, G.K., M.S. Kumar, and B.R. Wamhoff, Molecular regulation of vascularsmooth muscle cell differentiation in development and disease. Physiol Rev,2004.84(3):p.767-801.
    27. Cheng, Y., et al., MicroRNA-145, a novel smooth muscle cell phenotypic marker andmodulator, controls vascular neointimal lesion formation. Circ Res,2009.105(2): p.158-66.
    28. Cordes, K.R., et al., miR-145and miR-143regulate smooth muscle cell fate andplasticity. Nature,2009.460(7256): p.705-10.
    29. Boettger, T., et al., Acquisition of the contractile phenotype by murine arterial smoothmuscle cells depends on the Mir143/145gene cluster. J Clin Invest,2009.119(9): p.2634-47.
    30. Davis, B.N., et al., Induction of microRNA-221by platelet-derived growth factorsignaling is critical for modulation of vascular smooth muscle phenotype. J Biol Chem,2009.284(6): p.3728-38.
    31. Liu, X., et al., A necessary role of miR-221and miR-222in vascular smooth muscle cellproliferation and neointimal hyperplasia. Circ Res,2009.104(4): p.476-87.
    32. Miyazaki, M. and S. Takai,[Involvement of angiotensin II in development ofatherosclerosis]. Nihon Rinsho,2002.60(10): p.1904-10.
    33. Zhu, N., et al., Endothelial enriched microRNAs regulate angiotensin II-inducedendothelial inflammation and migration. Atherosclerosis,2011.215(2): p.286-93.
    34. Martin, M.M., et al., The human angiotensin II type1receptor+1166A/Cpolymorphism attenuates microrna-155binding. J Biol Chem,2007.282(33): p.24262-9.
    35. Martin, M.M., et al., MicroRNA-155regulates human angiotensin II type1receptorexpression in fibroblasts. J Biol Chem,2006.281(27): p.18277-84.
    36. Pasterkamp, G., J.K. Van Keulen, and D.P. De Kleijn, Role of Toll-like receptor4in theinitiation and progression of atherosclerotic disease. Eur J Clin Invest,2004.34(5): p.328-34.
    37. Chen, X.M., et al., A cellular micro-RNA, let-7i, regulates Toll-like receptor4expression and contributes to cholangiocyte immune responses againstCryptosporidium parvum infection. J Biol Chem,2007.282(39): p.28929-38.
    38. Liu, G., et al., miR-147, a microRNA that is induced upon Toll-like receptor stimulation,regulates murine macrophage inflammatory responses. Proc Natl Acad Sci U S A,2009.106(37): p.15819-24.
    39. Shan, Z.X., et al., Upregulated expression of miR-1/miR-206in a rat model ofmyocardial infarction. Biochem Biophys Res Commun,2009.381(4): p.597-601.
    40. Yu, X.Y., et al., Glucose induces apoptosis of cardiomyocytes via microRNA-1andIGF-1. Biochem Biophys Res Commun,2008.376(3): p.548-52.
    41. Yin, C., X. Wang, and R.C. Kukreja, Endogenous microRNAs induced by heat-shockreduce myocardial infarction following ischemia-reperfusion in mice. FEBS Lett,2008.582(30): p.4137-42.
    42. Xu, C., et al., The muscle-specific microRNAs miR-1and miR-133produce opposingeffects on apoptosis by targeting HSP60, HSP70and caspase-9in cardiomyocytes. JCell Sci,2007.120(Pt17): p.3045-52.
    43. O'Connell, R.M., et al., MicroRNA-155is induced during the macrophage inflammatoryresponse. Proc Natl Acad Sci U S A,2007.104(5): p.1604-9.
    44. Tili, E., et al., Modulation of miR-155and miR-125b levels followinglipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating theresponse to endotoxin shock. J Immunol,2007.179(8): p.5082-9.
    45. O'Connell, R.M., et al., Sustained expression of microRNA-155in hematopoietic stemcells causes a myeloproliferative disorder. J Exp Med,2008.205(3): p.585-94.
    46. Rodriguez, A., et al., Requirement of bic/microRNA-155for normal immune function.Science,2007.316(5824): p.608-11.
    47. Vigorito, E., et al., microRNA-155regulates the generation of immunoglobulinclass-switched plasma cells. Immunity,2007.27(6): p.847-59.
    48. Ceppi, M., et al., MicroRNA-155modulates the interleukin-1signaling pathway inactivated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A,2009.106(8): p.2735-40.
    49. Taganov, K.D., et al., NF-kappaB-dependent induction of microRNA miR-146, aninhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad SciU S A,2006.103(33): p.12481-6.
    50. Chen, T., et al., MicroRNA-125a-5p partly regulates the inflammatory response, lipiduptake, and ORP9expression in oxLDL-stimulated monocyte/macrophages. CardiovascRes,2009.83(1): p.131-9.
    51. Donners, M.M., et al., Hematopoietic miR155deficiency enhances atherosclerosis anddecreases plaque stability in hyperlipidemic mice. PLoS One,2012.7(4): p. e35877.
    52. Zhu, J., et al., Regulation of microRNA-155in atherosclerotic inflammatory responsesby targeting MAP3K10. PLoS One,2012.7(11): p. e46551.
    53. Nazari-Jahantigh, M., et al., MicroRNA-155promotes atherosclerosis by repressingBcl6in macrophages. J Clin Invest,2012.122(11): p.4190-202.
    54. Bonauer, A., et al., MicroRNA-92a controls angiogenesis and functional recovery ofischemic tissues in mice. Science,2009.324(5935): p.1710-3.
    55. Urbich, C., A. Kuehbacher, and S. Dimmeler, Role of microRNAs in vascular diseases,inflammation, and angiogenesis. Cardiovasc Res,2008.79(4): p.581-8.
    56. Kuehbacher, A., C. Urbich, and S. Dimmeler, Targeting microRNA expression toregulate angiogenesis. Trends Pharmacol Sci,2008.29(1): p.12-5.
    57. Wang, S. and E.N. Olson, AngiomiRs--key regulators of angiogenesis. Curr Opin GenetDev,2009.19(3): p.205-11.
    58. Kuehbacher, A., et al., Role of Dicer and Drosha for endothelial microRNA expressionand angiogenesis. Circ Res,2007.101(1): p.59-68.
    59. Fasanaro, P., et al., An integrated approach for experimental target identification ofhypoxia-induced miR-210. J Biol Chem,2009.284(50): p.35134-43.
    60. Tricot, O., et al., Relation between endothelial cell apoptosis and blood flow directionin human atherosclerotic plaques. Circulation,2000.101(21): p.2450-3.
    61. Mallat, Z. and A. Tedgui, Apoptosis in the vasculature: mechanisms and functionalimportance. Br J Pharmacol,2000.130(5): p.947-62.
    62. The muscle-specific microRNAs miR-1and miR-133produce opposing effects onapoptosis by targeting HSP60, HSP70and caspase-9in cardiomyocytes. J Cell Sci,2011.124(Pt18): p.3187.
    63. Wang, J.X., et al., miR-499regulates mitochondrial dynamics by targeting calcineurinand dynamin-related protein-1. Nat Med,2011.17(1): p.71-8.
    64. Wang, X., et al., MicroRNA-494targeting both proapoptotic and antiapoptotic proteinsprotects against ischemia/reperfusion-induced cardiac injury. Circulation,2010.122(13): p.1308-18.
    65. Hu, S., et al., MicroRNA-210as a novel therapy for treatment of ischemic heart disease.Circulation,2010.122(11Suppl): p. S124-31.
    66. Zhu, G.F., et al., miR-155inhibits oxidized low-density lipoprotein-induced apoptosis ofRAW264.7cells. Mol Cell Biochem,2013.
    67. Gironella, M., et al., Tumor protein53-induced nuclear protein1expression isrepressed by miR-155, and its restoration inhibits pancreatic tumor development. ProcNatl Acad Sci U S A,2007.104(41): p.16170-5.
    68. Meng, W., et al., Anti-miR-155oligonucleotide enhances chemosensitivity of U251cellto taxol by inducing apoptosis. Cell Biol Int,2012.
    69. Zheng, S.R., et al., Clinical significance of miR-155expression in breast cancer andeffects of miR-155ASO on cell viability and apoptosis. Oncol Rep,2012.27(4): p.1149-55.
    70. Kim, J.H., W.S. Kim, and C. Park, Epstein-Barr virus latent membrane protein-1protects B-cell lymphoma from rituximab-induced apoptosis through miR-155-mediatedAkt activation and up-regulation of Mcl-1. Leuk Lymphoma,2012.
    71. Ovcharenko, D., et al., Genome-scale microRNA and small interfering RNA screensidentify small RNA modulators of TRAIL-induced apoptosis pathway. Cancer Res,2007.67(22): p.10782-8.
    72. Pottier, N., et al., Identification of keratinocyte growth factor as a target ofmicroRNA-155in lung fibroblasts: implication in epithelial-mesenchymal interactions.PLoS One,2009.4(8): p. e6718.
    73. Lu, C., et al., miR-221and miR-155regulate human dendritic cell development,apoptosis, and IL-12production through targeting of p27kip1, KPC1, and SOCS-1.Blood,2011.117(16): p.4293-303.
    74. Esau, C., et al., miR-122regulation of lipid metabolism revealed by in vivo antisensetargeting. Cell Metab,2006.3(2): p.87-98.
    75. Nakanishi, N., et al., The up-regulation of microRNA-335is associated with lipidmetabolism in liver and white adipose tissue of genetically obese mice. BiochemBiophys Res Commun,2009.385(4): p.492-6.
    76. Poy, M.N., et al., A pancreatic islet-specific microRNA regulates insulin secretion.Nature,2004.432(7014): p.226-30.
    77. Rayner, K.J., et al., Inhibition of miR-33a/b in non-human primates raises plasma HDLand lowers VLDL triglycerides. Nature,2011.478(7369): p.404-7.
    78. Marquart, T.J., et al., Anti-miR-33therapy does not alter the progression ofatherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler ThrombVasc Biol,2013.33(3): p.455-8.
    79. van Rooij, E., W.S. Marshall, and E.N. Olson, Toward microRNA-based therapeutics forheart disease: the sense in antisense. Circ Res,2008.103(9): p.919-28.
    80. Silvestri, P., et al., MicroRNAs and ischemic heart disease: towards a bettercomprehension of pathogenesis, new diagnostic tools and new therapeutic targets.Recent Pat Cardiovasc Drug Discov,2009.4(2): p.109-18.
    81. Krutzfeldt, J., et al., Silencing of microRNAs in vivo with 'antagomirs'. Nature,2005.438(7068): p.685-9.
    82. Lanford, R.E., et al., Therapeutic silencing of microRNA-122in primates with chronichepatitis C virus infection. Science,2010.327(5962): p.198-201.