脂质、炎症在动脉粥样硬化发展机制中的研究进展

doi:10.3969/j.issn.1674-490X.2019.02.001

摘要/Abstract

摘要： 动脉粥样硬化(atherosclerosis,AS)是由脂质代谢失衡和动脉壁中含有胆固醇的巨噬细胞积聚驱动的适应不良免疫反应引起的一种慢性炎症性疾病。近年来,关于动脉粥样硬化发生机制的研究,主要包括脂质假说、炎症假说等。现主要对近几年动脉粥样硬化的发生机制进行整理归纳,并对动脉粥样硬化的药物治疗进行简单的论述。

关键词: 动脉粥样硬化, 脂质, 炎症

Abstract: Atherosclerosis(AS)is a chronic inflammatory disease caused by an imbalance in lipid metabolism and an adaptive immune response driven by the accumulation of cholesterol-containing macrophages in the arterial wall. In recent years, research on the mechanism of AS mainly includes lipid hypothesis, inflammation hypothesis and so on. This review mainly summarizes the mechanism of AS in recently years and briefly discusses the drug treatment of AS.

Key words: atherosclerosis, lipid, inflammation

中图分类号:

R543

马莹莹,傅继华. 脂质、炎症在动脉粥样硬化发展机制中的研究进展[J]. 医学研究与教育, 2019, 36(2): 1-7.

参考文献

[1] CHEN L Y, LEENING M J G, NORBY F L, et al. Carotid intima-media thickness and arterial stiffness and the risk of atrial fibrillation: the Atherosclerosis Risk in Communities(ARIC)study, Multi-Ethnic Study of Atherosclerosis(MESA), and the rotterdam study[J]. J Am Heart Assoc, 2016, 5(5):e002907. DOI: 10.1161/JAHA.115.002907.
[2] TOMIYAMA H, ISHIZU T, KOHRO T, et al. Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension[J]. Int J Cardiol, 2017, 253(2018):161-166. DOI: 10.1016/j.ijcard.2017.11.022.
[3] BENTZON J F, OTSUKA F, VIRMANI R, et al. Mechanisms of plaque formation and rupture[J]. Circ Res, 2014, 114(12):1852-1866. DOI: 10.1161/CIRCRESAHA.114.302721.
[4] GOLDSTEIN J L, BROWN M S. A century of cholesterol and coronaries: from plaques to genes to statins[J]. Cell, 2015, 161(1):161-172. DOI: 10.1016/j.cell.2015.01.036.
[5] LIBBY P, RIDKER P M, HANSSON G K. Progress and challenges in translating the biology of atherosclerosis[J]. Nature, 2011, 473(7347):317-325. DOI: 10.1038/nature10146.
[6] SUBRAMANIAN M, TABAS I. Dendritic cells in atherosclerosis[J]. Semin Immunopathol, 2014, 36(1):93-102. DOI: 10.1007/s00281-013-0400-x.
[7] LEITINGER N, SCHULMAN I G. Phenotypic polarization of macrophages in atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2013, 33(6):1120-1126. DOI: 10.1161/ATVBAHA.112.300173.
[8] CHOROMAN 'SKA B, MYS 'LIWIEC P, CHOROMAN 'SKA K, et al. The role of CD36 receptor in the pathogenesis of atherosclerosis[J]. Adv Clin Exp Med,2017, 26(4):717-722. DOI: 10.17219/acem/62325.
[9] SILVERSTEIN R L, LI W, PARK Y M, et al. Mechanisms of cell signaling by the scavenger receptor CD36: implications in atherosclerosis and thrombosis[J]. Trans Am Clin Climatol Assoc, 2010, 121:206-220.
[10] MANNING-TOBIN J J, MOORE K J, SEIMON T A, et al. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice[J]. Arterioscler Thromb Vasc Biol, 2009, 29(1):19-26. DOI: 10.1161/ATVBAHA.108.176644.
[11] KENNEDY D J, KUCHIBHOTLA S, WESTFALL K M, et al. A CD36-dependent pathway enhances macrophage and adipose tissue inflammation and impairs insulin signalling[J]. Cardiovasc Res, 2011, 89(3):604-613. DOI: 10.1093/cvr/cvq360.
[12] CHÁVEZ-SÁNCHEZ L, GARZA-REYES M G, ESPINOSA-LUNA J E, et al. The role of TLR2, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans[J]. Hum Immunol, 2014, 75(4):322-329. DOI: 10.1016/j.humimm.2014.01.012.
[13] TRPKOVIC A, RESANOVIC I, STANIMIROVIC J, et al. Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases[J]. Crit Rev Clin Lab Sci, 2015, 52(2):1-16. DOI: 10.3109/10408363.2014.992063.
[14] SEIMON T A, NADOLSKI M J, LIAO X, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress[J]. Cell Metabolism, 2010, 12(5):467-482. DOI: 10.1016/j.cmet.2010.09.010.
[15] MITRA S, DESHMUKH A, SACHDEVA R, et al. Oxidized low-density lipoprotein and atherosclerosis implications in antioxidant therapy[J]. Am J Med Sci, 2011, 342(2):135-142. DOI: 10.1097/MAJ.0b013e318224a147.
[16] YANG H, MOHAMED A S, ZHOU S H. Oxidized low density lipoprotein, stem cells, and atherosclerosis[J]. Lipids Health Dis, 2012, 11(1): 85-93. DOI: 10.1186/1476-511X-11-85.
[17] ROSS R. Atherosclerosis — An inflammatory disease[J]. N Engl J Med, 1999, 340(2):115-126. DOI: 10.1056/NEJM199901143400207.
[18] WEBER C, ZERNECKE A, LIBBY P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models[J]. Nat Rev Immunol, 2008, 8(10):802-815. DOI: 10.1038/nri2415.
[19] LIBBY P, LICHTMAN A H, HANSSON G K. Immune effector mechanisms implicated in atherosclerosis: from mice to humans[J]. Immunity, 2013, 38(6):1092-1104. DOI: 10.1016/j.immuni.2013.06.009.
[20] TAKEUCHI O, AKIRA S. Pattern recognition receptors and inflammation[J]. Cell, 2010, 140(6):805-820. DOI: 10.1016/j.cell.2010.01.022.
[21] LEE J G, LIM E J, PARK D W, et al. A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation[J]. Cell Signal, 2008, 20(12):2266-2275. DOI: 10.1016/j.cellsig.2008.08.022.
[22] HIGASHIMORI M, TATRO J B, MOORE K J, et al. Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice[J]. Arterioscl Throm Vasc Biol, 2011, 31(1):50-57. DOI: 10.1161/ATVBAHA.110.210971.
[23] SENEVIRATNE A N, MONACO C. Role of inflammatory cells and toll-like receptors in atherosclerosis[J]. Curr Vasc Pharmacol, 2013, 13(2):146-160. DOI: 10.2174/15701611113116660160.
[24] DEN DEKKER W K, CHENG C, PASTERKAMP G, et al. Toll like receptor 4 in atherosclerosis and plaque destabilization[J]. Atherosclerosis, 2010, 209(2):314-320. DOI: 10.1016/j.atherosclerosis.2009.09.075.
[25] HAZEN S L. Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity[J]. J Biol Chem, 2008, 283(23):15527-15531. DOI: 10.1074/jbc.R700054200.
[26] ROSS R, GLOMSET J, HARKER L A. Response to injury and atherogenesis[J]. Am J Pathol, 1977, 86(3):674-684.
[27] ASSEMAT P, SIU K K, ARMITAGE J A, et al. Haemodynamical stress in mouse aortic arch with atherosclerotic plaques: preliminary study of plaque progression[J]. Comput Struct Biotechnol J, 2014, 10(17):98-106. DOI: 10.1016/j.csbj.2014.07.004.
[28] IMANISHI T, AKASAKA T. Biomarkers associated with vulnerable atheromatous plaque[J]. Curr Med Chem, 2012, 19(16):2588-2596. DOI: 10.2174/092986712800492922.
[29] FAGERBERG B, RYNDEL M, KJELLDAHL J, et al. Differences in lesion severity and cellular composition between in vivo assessed upstream and downstream sides of human symptomatic carotid atherosclerotic plaques[J]. J Vasc Res, 2010, 47(3):221-230. DOI: 10.1159/000255965.
[30] HANSSON G K, ROBERTSON A K, SÖDERBERG-NAUCLÉR C. Inflammation and atherosclerosis[J]. Annu Rev Pathol, 2006, 1:297-329. DOI: 10.1016/j.ejvs.2005.11.001.
[31] PERTICONE F, MAIO R, SCIACQUA A, et al. Endothelial dysfunction and C-reactive protein are risk factors for diabetes in essential hypertension[J]. Diabetes, 2008, 57(1):167-171. DOI: 10.2337/db07-1189.
[32] GILLHAM J, MYERS J E, BAKER P N, et al. TNF-alpha alters nitric oxide- and endothelium-derived hyperpolarizing factor-mediated vasodilatation in human omental arteries[J]. Hypertens Pregnancy, 2008, 27(1):29-38. DOI: 10.1080/10641950701825796.
[33] FAIRAQ A, GOC A, ARTHAM S, et al. TNFα induces inflammatory stress response in microvascular endothelial cells via Akt-and P38 MAP kinase-mediated thrombospondin-1 expression[J]. Mol Cell Biochem, 2015, 406(1-2):227-236. DOI: 10.1007/s11010-015-2440-0.
[34] HUSAIN K, SUAREZ E, ISIDRO A, et al. Effects of paricalcitol and enalapril on atherosclerotic injury in mouse aortas[J]. Am J Nephrol, 2010, 32(4):296-304. DOI: 10.1159/000319445.
[35] SUAREZ-MARTINEZ E, HUSAIN K, FERDER L. Adiponectin expression and the cardioprotective role of the vitamin D receptor activator paricalcitol and the angiotensin converting enzyme inhibitor enalapril in ApoE-deficient mice[J]. Ther Adv Cardiovasc Dis, 2014, 8(6):224-236. DOI: 10.1177/1753944714542593.
[36] WANG Y, WANG G Z, RABINOVITCH P S, et al. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages[J]. Circ Res, 2014, 114(3):421-433.
[37] SPITE M, SERHAN C N. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins[J]. Circ Res, 2010, 107(10):1170-1184. DOI: 10.1161/CIRCRESAHA.110.223883.
[38] MAGGIO A B, WACKER J, MONTECUCCO F, et al. Serum resistin and inflammatory and endothelial activation markers in obese adolescents[J]. J Pediatr, 2012, 161(6):1022-1027. DOI: 10.1016/j.jpeds.2012.05.063.
[39] HSU W Y,CHAO Y W,TSAI Y L, et al. Resistin induces monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression in endothelial cells via p38MAPK-dependent pathway[J]. J Cell Physiol, 2011, 226(8):2181-2188. DOI: 10.1002/jcp.22555.
[40] STRABURZYN 'SKA-LUPA A, NOWAK A, PILACZYN 'SKA-SZCZES 'NIAK L, et al. Visfatin, resistin, hsCRP and insulin resistance in relation to abdominal obesity in women with rheumatoid arthritis[J]. Clin Exp Rheumatol, 2010, 28(1):19-24. DOI:10.1186/ar2917.
[41] HUSAIN K, HERNANDEZ W, ANSARI R A, et al. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis[J]. World J Biol Chem, 2015, 6(3):209-217. DOI:10.4331/wjbc.v6.i3.209.
[42] ROSENSON R S, ELLIOTTM, STASIV Y, et al. Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease[J]. Eur Heart J, 2011, 32(8):999-1005. DOI: 10.1093/eurheartj/ehq374.
[43] STEWART R A, WHITE H D. The role of lipoprotein-associated phospholipase a₂ as a marker and potential therapeutic target in atherosclerosis[J]. Curr Atheroscler Rep, 2011, 13(2):132-137. DOI: 10.1007/s11883-010-0158-8.
[44] GAZTANAQA J, FARKOUH M, RUDD J H, et al. A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome[J]. Atherosclerosis, 2015, 240(1):53-60. DOI: 10.1016/j.atherosclerosis.2015.02.027.
[45] GILBERT J, LEKSTROM-HIMES J, DONALDSON D, et al. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region[J]. Am J Cardiol, 2011, 107(6):906-911. DOI: 10.1016/j.amjcard.2010.11.005.
[46] RIDKER P M. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial(CIRT)[J]. J Thromb Haemost, 2009, 7(Suppl 1):332-339. DOI: 10.1111/j.1538-7836.2009.03404.x.
[47] CROSSMAN D C, MORTON A C, GUNN J P, et al. Investigation of the effect of Interleukin-1 receptor antagonist(IL-1ra)on markers of inflammation in non-ST elevation acute coronary syndromes(The MRC-ILA-HEART Study)[J]. Trials, 2008, 9(1):8-21. DOI: 10.1186/1745-6215-9-8.
[48] XU Y J,ZHANG M,JI L,et al. Suppression of high lipid diet induced by atherosclerosis sarpogrelate[J]. J Cell Mol Med, 2012, 16(10):2394-2400. DOI: 10.1111/j.1582-4934.2012.01554.x.