纤维化对动脉粥样硬化斑块稳定性的基础研究及相关药物应用
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摘要
在目前心血管疾病高发高致死的背景下,动脉粥样硬化是心血管系统疾病的主要病理特征和驱动疾病进展的核心病理基础。不稳定斑块的破裂以及斑块脱落、血栓形成是动脉粥样硬化过程中最具危险性的环节。其中斑块纤维化的形成是调节斑块稳定性的核心机制。更重要的是,纤维化反映了炎症进程的动态性变化以及病理性改变。该文从炎症调节与纤维化调节2个方面入手,审视了动脉粥样硬化斑块进程,归纳了炎症相关细胞和细胞因子在斑块稳定性中发挥的作用,并对近年来与稳定斑块相关的中药研究进行概述,为未来从纤维化角度改善斑块稳定性的药物开发提供新思路。
In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the core pathological basis for disease progression. In the evolution of atherosclerotic plaques,the rupture of unstable plaques,plaque shedding and formation of thrombosis are the most dangerous parts. In this process,the formation of plaque fibrosis is the core mechanism regulating plaque stability. Additionally,fibrosis reflects dynamic changes in the inflammatory processes and pathological changes. In view of the inflammation regulation and fibrosis regulation,this paper clarified the process of atherosclerotic plaque,explained the roles of relevant inflammatory cells and cytokines in plaque stability,and summed up drug researches related with stable plaque in recent years. In the future,improving the fibrosis will be a new idea for stabilizing plaque in atherosclerosis drug development.
In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the core pathological basis for disease progression. In the evolution of atherosclerotic plaques,the rupture of unstable plaques,plaque shedding and formation of thrombosis are the most dangerous parts. In this process,the formation of plaque fibrosis is the core mechanism regulating plaque stability. Additionally,fibrosis reflects dynamic changes in the inflammatory processes and pathological changes. In view of the inflammation regulation and fibrosis regulation,this paper clarified the process of atherosclerotic plaque,explained the roles of relevant inflammatory cells and cytokines in plaque stability,and summed up drug researches related with stable plaque in recent years. In the future,improving the fibrosis will be a new idea for stabilizing plaque in atherosclerosis drug development.
引文
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[3]吕树铮,赵全明.动脉粥样硬化易损斑块的诊断和治疗[M].北京:人民卫生出版社,2009:9.
[4] Kasikara C,Doran A C,Cai B,et al. The role of non-resolving inflammation in atherosclerosis[J]. J Clin Invest,2018,128(7):2713.
[5] E Galkina,K Ley. Immune and inflammatory mechanisms of atherosclerosis[J]. Annu Rev Immunol,2009,27:165.
[6] Spacek M,Zemanek D,Hutyra M,et al. Vulnerable atherosclerotic plaque-a review of current concepts and advanced imaging[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2018,162(1):10.
[7] Sanz J,Moreno P R,Fuster V. The year in atherothrombosis[J].J Am Coll Cardiol,2012,60(10):932.
[8] D W Gilroy,T Lawrence,M Perretti,et al. Inflammatory resolution:new opportunities for drug discovery[J]. Nat Rev Drug Discov,2004,3(5):401.
[9]周光妍,于波.冠状动脉易损斑块形成机制研究进展[J].中华老年多器官疾病杂志,2018,17(2):153.
[10] Ryan M Pedrigi,Ranil de Silva,Sandra M Bovens,et al. Thincap fibroatheroma rupture is associated with a fine interplay of shear and wall[J]. Arterioscler Thromb Vasc Biol,2014,34:2224.
[11] Lan T H,Huang X Q,Tan H M. Vascular fibrosis in atherosclerosis[J].Cardiovasc Pathol,2013,22(5):401.
[12] Tuccori M,Montagnani S,Mantarro S. Neuropsychiatric adverse events associated with statins:epidemiology, pathophysiology,prevention and management[J]. CNS Drugs,2014,28(3):249.
[13] Woessner K M,Simon R A. Cardiovascular prophylaxis and aspirin"allergy"[J]. Immunol Allergy Clin North Am,2013,33(2):263.
[14] Virmani R,Burke AP,Farb A,et al. Pathology of the vulnerable plaque[J]. J Am Coll Cardiol,2006,47(8 Suppl):C13.
[15] Waxman S,Ishibashi F,Muler J E. Detection and treatment of vulnerable plaques and vulnerable patients:novel approaches to prevention of coronary events[J]. Circulation,2006,114(22):2390.
[16] Ross R. Atherosclerosis-an inflammatory disease[J]. N Engl J Med,1993,340(2):115.
[17] Pant S,Deshmukh A,Gurumurthy G S,et al. Inflammation and atherosclerosis-revisited[J]. J Cardiovasc Pharmacol Ther,2014,19(2):170.
[18] Ira Tabas,Karin E Bornfeldt. Macrophage phenotype and function in different stages of atherosclerosis[J]. Circ Res,2016,118(4):653.
[19] Martin R Bennett,Sanjay Sinha,Gary K Owens. Vascular smooth muscle cells in atherosclerosis[J]. Circ Res,2016,118(4):692.
[20] Susanne Feil,Birgit Fehrenbacher,Robert Lukowski, et al.Trans differentiation of vascular smooth muscle cells to macrophage-like cells during atherosclerosis[J]. Circ Res,2014,115:662.
[21] Butoi E,Gan A M,Tucureanu M M,et al. Cross-talk between macrophages and smooth muscle cells impairs collagen and metalloprotease synthesis and promotes angiogenesis[J] Biochim Biophys Acta,2016,1683(7):1568.
[22] Virmani R,Kolodgie F D,Burke A P,et al. Lessons from sudden coronary death:a comprehensive morphological classification scheme for atherosclerotic lesions[J]. Arterioscler Thromb Vasc Biol,2000,20(5):1262.
[23] Caligiuri G,Rudling M,Ollivier V,et al. lesions and Th17 in interleukin-10 deficiency increases atherosclerosis,thrombosis,and low-density lipoproteins in apolipoprotein E-knockout mice[J]. Mol Med,2003,9(1/2):10.
[24] J Viola,O Soehnlein. Atherosclerosis-a matter of unresolved inflammation[J]. Semin Immunol,2015,27(3):184.
[25] M A Sugimoto,L P Sousa,V Pinho,et al. Resolution of inflammation:what controls its onset?[J]. Front Immunol,2016,7:160.
[26] M P Motwani,D W Gilroy. Macrophage development and polarization in chronic inflammation[J]. Semin Immunol,2015,27(4):257.
[27] Liu Y C,Zou X B,Chai Y F,et al. Macrophage polarization in inflammatory diseases[J]. Int J Biol Sci,2014,10(5):520.
[28] Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis[J]. Nat Rev Immunol,2010,10(1):36.
[29] Osonoi Y,Mita T,Azuma K,et al,Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis[J]. Autophagy,2018,14(11):1991.
[30] Winkels H,Weber C,Lutgens E,et al,Atherosclerosis:cell biology and lipoproteins focus on i NKT cells and CD40/CD40L in atherosclerosis and metabolic disorders[J]. Curr Opin Lipidol,2014,25(5):408.
[31] Evangelia Pardali,Peter ten Dijke. TGF-β:signaling and cardiovascular diseases[J].Int J Biol Sci,2012,8(2):195.
[32] Ian Toma,Timothy A Mc Caffrey. Transforming growth factor-βand atherosclerosis:interwoven[J]. Cell Tissue Res,2012,347(1):155.
[33] Ravandi A,Leibundgut G,Hung M Y,et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans[J]. J Am Coll Cardiol,2014,63(19):1961.
[34] Lin J,Kakkar V,Lu X. Impact of matrix metalloproteinases on atherosclerosis[J]. Curr Drug Targets,2014,15(4):442.
[35] P K Shah. Biomarkers of plaque instability[J]. Curr Cardiol Rep,2014,16:547.
[36]王显.急性冠脉综合征与动脉粥样硬化“络风内动”假说[J].中国医院用药评价与分析,2012,11(9):771.
[37]唐雅玲,黄韬,杨永宗,等.普罗布考对新西兰兔动脉粥样硬化的影响[J].天津医药,2012,40(1):50.
[38]周昱,张长翼.丹参酮ⅡA联辛伐他汀治疗颈动脉粥样硬化的疗效观察[J].汕头大学医学院学报,2015,28(1):19.
[39]金娟,刘莉,李志鸿.丹参酮对血瘀证患者颈动脉粥样硬化斑块及血清超敏C反应蛋白的影响[J].中医药学报,2012,40(3):69.
[40]薛偕华,魏伟,陈彤,等.泽泻汤对巨噬细胞泡沫化脂质沉积及其LXRα和ABCA1表达的影响[J].中国动脉硬化杂志,2013,21(11):971.
[41]刘美霞.急性冠脉综合征瘀毒证及解毒活血抗动脉粥样硬化的分子机制研究[D].广州:广东中医药大学,2010.
[42] Zhong L,Chen W Q,Ji X P,et al. Dominant-negative mutation of monocyte chemoattractant protein-1 prevents vulnerable plaques from rupture in rabbits independent of serum lipid levels[J]. J Cell Mol Med,2008,12(6A):2362.
[43]白会强.补阳还五汤抗动脉粥样硬化炎症机制及对炎性细胞因子表达谱的影响[D].广州:南方医科大学,2009.
[44]龙铟,刘家云,王宗仁.芪丹通脉片对冠心病患者炎症因子的影响[J].微循环学杂志,2012,22(2):90.
[45]周凤华,黄志勇,娄林洁,等.葛根素抗ApoE-/-小鼠动脉粥样硬化的炎症机制研究[J].中药药理与临床,2013,29(5):33.
[46]关启刚,曾定尹,孙喜琢,等.通心络抑制白细胞介素1β介导的小型猪冠状动脉早期炎症反应及内膜增殖[J].中国动脉硬化杂志,2007,5(2):265.
[47]庞荣清,周平,潘兴华,等.灯盏花素对动脉粥样硬化兔内皮素、一氧化氮、超氧化物歧化酶、丙二醛分泌水平的影响[J].中国比较医学杂志,2008(10):75.
[48]贾连群,杨关林,任路,等.化瘀祛痰方药对H2O2诱导人脐带静脉内皮细胞氧化应激保护作用的研究[J].中国中医药信息杂志,2011,8(9):44.
[49]王学莉,顾振纶,王道生.复方丹参滴丸干预大鼠心肌再灌注损伤的机制研究[J].中西医结合心脑血管病杂志,2006,4(9):789.
[50]杨艳秋,杨伟民,曹淑杰,等.当归活性成分阿魏酸钠干预老年冠状动脉粥样硬化性心脏病心绞痛患者血液抗氧化能力和保护血内皮细胞功能[J].中国临床康复,2006(39):101.
[51] Johnson J L. Matrix metalloproteinases:influence on smooth muscle cells and atherosclerotic plaque stability[J]. Expert Rev Cardiovasc Ther,2007,5(2):265.
[52]郭茂娟,马东明,卢斌,等.心脑血脉宁对家兔动脉粥样硬化易损斑块模型MMP-2、TIMP-2表达的影响[J].天津中医药,2010,27(2):150.
[53]玄昌波,王显.动脉粥样硬化易损斑块中医药干预机制研究概况[J].中医杂志,2014,55(18):1607.
[54]祝骥,许颖龄,卢德赵,等.复方丹参片对颈动脉粥样硬化兔PPAR-γ/LXR-α/ABCA1信号通路的影响[J].中国现代应用药学,2016,33(12):1503.
[55]文川,徐浩. 6种活血中药对ApoE基因缺陷小鼠动脉粥样硬化斑块胶原沉积及代谢的影响[J].中国中医基础医学杂志,2012,18(5):550.
[56]万新红,郭洪波.参七黄稳斑胶囊对兔动脉粥样硬化斑块稳定性的影响[J].中国中医急症,2009,18(8):1295.
[57]赵玉霞,刘运芳,刘艳,等.祛瘀消斑胶囊对易损斑块的稳定作用[J].中医杂志,2006(11):856.
[2]陈伟伟,高润霖,刘力生,等.《中国心血管病报告2017》概要[J].中国循环杂志,2018,33(1):1.
[3]吕树铮,赵全明.动脉粥样硬化易损斑块的诊断和治疗[M].北京:人民卫生出版社,2009:9.
[4] Kasikara C,Doran A C,Cai B,et al. The role of non-resolving inflammation in atherosclerosis[J]. J Clin Invest,2018,128(7):2713.
[5] E Galkina,K Ley. Immune and inflammatory mechanisms of atherosclerosis[J]. Annu Rev Immunol,2009,27:165.
[6] Spacek M,Zemanek D,Hutyra M,et al. Vulnerable atherosclerotic plaque-a review of current concepts and advanced imaging[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2018,162(1):10.
[7] Sanz J,Moreno P R,Fuster V. The year in atherothrombosis[J].J Am Coll Cardiol,2012,60(10):932.
[8] D W Gilroy,T Lawrence,M Perretti,et al. Inflammatory resolution:new opportunities for drug discovery[J]. Nat Rev Drug Discov,2004,3(5):401.
[9]周光妍,于波.冠状动脉易损斑块形成机制研究进展[J].中华老年多器官疾病杂志,2018,17(2):153.
[10] Ryan M Pedrigi,Ranil de Silva,Sandra M Bovens,et al. Thincap fibroatheroma rupture is associated with a fine interplay of shear and wall[J]. Arterioscler Thromb Vasc Biol,2014,34:2224.
[11] Lan T H,Huang X Q,Tan H M. Vascular fibrosis in atherosclerosis[J].Cardiovasc Pathol,2013,22(5):401.
[12] Tuccori M,Montagnani S,Mantarro S. Neuropsychiatric adverse events associated with statins:epidemiology, pathophysiology,prevention and management[J]. CNS Drugs,2014,28(3):249.
[13] Woessner K M,Simon R A. Cardiovascular prophylaxis and aspirin"allergy"[J]. Immunol Allergy Clin North Am,2013,33(2):263.
[14] Virmani R,Burke AP,Farb A,et al. Pathology of the vulnerable plaque[J]. J Am Coll Cardiol,2006,47(8 Suppl):C13.
[15] Waxman S,Ishibashi F,Muler J E. Detection and treatment of vulnerable plaques and vulnerable patients:novel approaches to prevention of coronary events[J]. Circulation,2006,114(22):2390.
[16] Ross R. Atherosclerosis-an inflammatory disease[J]. N Engl J Med,1993,340(2):115.
[17] Pant S,Deshmukh A,Gurumurthy G S,et al. Inflammation and atherosclerosis-revisited[J]. J Cardiovasc Pharmacol Ther,2014,19(2):170.
[18] Ira Tabas,Karin E Bornfeldt. Macrophage phenotype and function in different stages of atherosclerosis[J]. Circ Res,2016,118(4):653.
[19] Martin R Bennett,Sanjay Sinha,Gary K Owens. Vascular smooth muscle cells in atherosclerosis[J]. Circ Res,2016,118(4):692.
[20] Susanne Feil,Birgit Fehrenbacher,Robert Lukowski, et al.Trans differentiation of vascular smooth muscle cells to macrophage-like cells during atherosclerosis[J]. Circ Res,2014,115:662.
[21] Butoi E,Gan A M,Tucureanu M M,et al. Cross-talk between macrophages and smooth muscle cells impairs collagen and metalloprotease synthesis and promotes angiogenesis[J] Biochim Biophys Acta,2016,1683(7):1568.
[22] Virmani R,Kolodgie F D,Burke A P,et al. Lessons from sudden coronary death:a comprehensive morphological classification scheme for atherosclerotic lesions[J]. Arterioscler Thromb Vasc Biol,2000,20(5):1262.
[23] Caligiuri G,Rudling M,Ollivier V,et al. lesions and Th17 in interleukin-10 deficiency increases atherosclerosis,thrombosis,and low-density lipoproteins in apolipoprotein E-knockout mice[J]. Mol Med,2003,9(1/2):10.
[24] J Viola,O Soehnlein. Atherosclerosis-a matter of unresolved inflammation[J]. Semin Immunol,2015,27(3):184.
[25] M A Sugimoto,L P Sousa,V Pinho,et al. Resolution of inflammation:what controls its onset?[J]. Front Immunol,2016,7:160.
[26] M P Motwani,D W Gilroy. Macrophage development and polarization in chronic inflammation[J]. Semin Immunol,2015,27(4):257.
[27] Liu Y C,Zou X B,Chai Y F,et al. Macrophage polarization in inflammatory diseases[J]. Int J Biol Sci,2014,10(5):520.
[28] Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis[J]. Nat Rev Immunol,2010,10(1):36.
[29] Osonoi Y,Mita T,Azuma K,et al,Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis[J]. Autophagy,2018,14(11):1991.
[30] Winkels H,Weber C,Lutgens E,et al,Atherosclerosis:cell biology and lipoproteins focus on i NKT cells and CD40/CD40L in atherosclerosis and metabolic disorders[J]. Curr Opin Lipidol,2014,25(5):408.
[31] Evangelia Pardali,Peter ten Dijke. TGF-β:signaling and cardiovascular diseases[J].Int J Biol Sci,2012,8(2):195.
[32] Ian Toma,Timothy A Mc Caffrey. Transforming growth factor-βand atherosclerosis:interwoven[J]. Cell Tissue Res,2012,347(1):155.
[33] Ravandi A,Leibundgut G,Hung M Y,et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans[J]. J Am Coll Cardiol,2014,63(19):1961.
[34] Lin J,Kakkar V,Lu X. Impact of matrix metalloproteinases on atherosclerosis[J]. Curr Drug Targets,2014,15(4):442.
[35] P K Shah. Biomarkers of plaque instability[J]. Curr Cardiol Rep,2014,16:547.
[36]王显.急性冠脉综合征与动脉粥样硬化“络风内动”假说[J].中国医院用药评价与分析,2012,11(9):771.
[37]唐雅玲,黄韬,杨永宗,等.普罗布考对新西兰兔动脉粥样硬化的影响[J].天津医药,2012,40(1):50.
[38]周昱,张长翼.丹参酮ⅡA联辛伐他汀治疗颈动脉粥样硬化的疗效观察[J].汕头大学医学院学报,2015,28(1):19.
[39]金娟,刘莉,李志鸿.丹参酮对血瘀证患者颈动脉粥样硬化斑块及血清超敏C反应蛋白的影响[J].中医药学报,2012,40(3):69.
[40]薛偕华,魏伟,陈彤,等.泽泻汤对巨噬细胞泡沫化脂质沉积及其LXRα和ABCA1表达的影响[J].中国动脉硬化杂志,2013,21(11):971.
[41]刘美霞.急性冠脉综合征瘀毒证及解毒活血抗动脉粥样硬化的分子机制研究[D].广州:广东中医药大学,2010.
[42] Zhong L,Chen W Q,Ji X P,et al. Dominant-negative mutation of monocyte chemoattractant protein-1 prevents vulnerable plaques from rupture in rabbits independent of serum lipid levels[J]. J Cell Mol Med,2008,12(6A):2362.
[43]白会强.补阳还五汤抗动脉粥样硬化炎症机制及对炎性细胞因子表达谱的影响[D].广州:南方医科大学,2009.
[44]龙铟,刘家云,王宗仁.芪丹通脉片对冠心病患者炎症因子的影响[J].微循环学杂志,2012,22(2):90.
[45]周凤华,黄志勇,娄林洁,等.葛根素抗ApoE-/-小鼠动脉粥样硬化的炎症机制研究[J].中药药理与临床,2013,29(5):33.
[46]关启刚,曾定尹,孙喜琢,等.通心络抑制白细胞介素1β介导的小型猪冠状动脉早期炎症反应及内膜增殖[J].中国动脉硬化杂志,2007,5(2):265.
[47]庞荣清,周平,潘兴华,等.灯盏花素对动脉粥样硬化兔内皮素、一氧化氮、超氧化物歧化酶、丙二醛分泌水平的影响[J].中国比较医学杂志,2008(10):75.
[48]贾连群,杨关林,任路,等.化瘀祛痰方药对H2O2诱导人脐带静脉内皮细胞氧化应激保护作用的研究[J].中国中医药信息杂志,2011,8(9):44.
[49]王学莉,顾振纶,王道生.复方丹参滴丸干预大鼠心肌再灌注损伤的机制研究[J].中西医结合心脑血管病杂志,2006,4(9):789.
[50]杨艳秋,杨伟民,曹淑杰,等.当归活性成分阿魏酸钠干预老年冠状动脉粥样硬化性心脏病心绞痛患者血液抗氧化能力和保护血内皮细胞功能[J].中国临床康复,2006(39):101.
[51] Johnson J L. Matrix metalloproteinases:influence on smooth muscle cells and atherosclerotic plaque stability[J]. Expert Rev Cardiovasc Ther,2007,5(2):265.
[52]郭茂娟,马东明,卢斌,等.心脑血脉宁对家兔动脉粥样硬化易损斑块模型MMP-2、TIMP-2表达的影响[J].天津中医药,2010,27(2):150.
[53]玄昌波,王显.动脉粥样硬化易损斑块中医药干预机制研究概况[J].中医杂志,2014,55(18):1607.
[54]祝骥,许颖龄,卢德赵,等.复方丹参片对颈动脉粥样硬化兔PPAR-γ/LXR-α/ABCA1信号通路的影响[J].中国现代应用药学,2016,33(12):1503.
[55]文川,徐浩. 6种活血中药对ApoE基因缺陷小鼠动脉粥样硬化斑块胶原沉积及代谢的影响[J].中国中医基础医学杂志,2012,18(5):550.
[56]万新红,郭洪波.参七黄稳斑胶囊对兔动脉粥样硬化斑块稳定性的影响[J].中国中医急症,2009,18(8):1295.
[57]赵玉霞,刘运芳,刘艳,等.祛瘀消斑胶囊对易损斑块的稳定作用[J].中医杂志,2006(11):856.
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