1、三酯OCHCH2OCR1OCR2OCH2OCOR3CH3CH3CH3CH3CH3CH3乳糜微粒Doi H et al.Circulation 2000;102:670-676;Colome C et al.Atherosclerosis 2000;149:295-302;Cockerill GW et al.Arterioscler Thromb Vasc Biol 1995;15:1987-1994.Murphy HC et al.Biochemistry 2000;39:9763-970.Rye KA et al.Atherosclerosis 1999;145:227-238.Rye K
2、A et al.Atherosclerosis 1999;145:227-238.CH3-(CH2)7-CH=CH-(CH2)7-C-O-CHCH2-O-C-(CH2)14-CH3 O CH2-O-C-(CH2)16-CH3 O OOCHCH2OCR1OCR2OCH2OCOR3HOCHCH2OHCH2OHCH2CH2CH2RCOSCoACOSCoACHCHCH2RCH2COSCoACHCH2ROHCH2COSCoACCH2ROCH3COSCoACH2CH2CH2Rn-2COSCoANHCH2CH2CONHCH2CH2SHOPOCH2CCHCOCH3CH3OHOHOCH2CHHNCOCOCH3S
3、CoAATPADP,PiCO2acetyl CoAacetyl CoA carboxylaseCOCH2SCoACOOHmalonyl CoACOCH2SACPCOOHCoASHacyl transferasemalonyl acyl carrier proteinACP-SHCO2-keto-acyl ACP synthaseCOCH2SACPCCH2ORNADPHNADP+COCH2SACPHCCH2ROH-keto-acyl ACPreductaseH2OCOCHSACPCHCH2R-hydroxy-acyl ACPdehydrataseNADPHNADP+COCH2SACPCH2CH2
4、Renoyl ACPreductaseketo-acyl ACPhydroxy-acyl ACPenoyl ACPfatty acyl ACPCH2RCSOACPfatty acyl ACPCH3CH3CH3CH3CH3CH3CellMembraneLiverPeripheraltissuesVLDL,IDL,LDLLDL receptorLCATCETPFCCECETGTGCEHDLHDLFree cholesterol(FC)TriglyceridesCholesterol estersCETP Cholesteryl ester transfer proteinLCATLecithin
5、cholesterol acyltransferaseSR-BIAIC-II C-IEEAIIAIIAII EE洛杉矶退伍军人研究(Los Angeles Veterans Study,LAVS)奥斯陆一级预防试验(Oslo Primary Prevention Trial)多危险因素干预试验(MRFIT)欧洲协作研究(The European Collaborative Trial)饮食与再梗死试验(DART)手术控制高脂血症试验(POSCH)血脂研究临床中心与CHD一级预防试验(Lipid Research Clinics Coronary Primary Prevention Trial
6、)(LRC-CPPT)冠心病干预研究(Coronary InterventionsStudy,CIS)降低胆固醇与的动脉粥样硬化研究之一(Cholesterol-Lowering Atherosclerosis Study,CLAS-I)降低胆固醇与的动脉粥样硬化研究之二(Cholesterol-Lowering Atherosclerosis Study,CLAS-II)圣托马斯粥样硬化消退研究(St Thomas Atherosclerosis Regression Study,STARS)冠心病药物治疗方案(coronary Drug Project,CDP)家族性动脉粥样硬化治疗研究(
7、FATS)监测动脉粥样硬化消退研究(MARS)无症状性颈动脉斑块研究(ACAPS)老年人降胆固醇计划(CRISP)加拿大冠状动脉粥样硬化干预试验(CCAIT)空军得州克萨斯冠状动脉粥样硬化预防研究(AFCAPS/TexCAPS)北欧辛伐他汀生存研究(4S)多中心抗动脉粥样瘤研究(MAAS)普伐他汀对冠心病患者冠状动脉粥样病变消退影响的研究(REGRESS)Kuopio动脉粥样硬化预防研究(KAPS)西苏格兰冠心病预防研究(WOSCOPS)普伐他汀限制冠状动脉粥样硬化I(PLAC I)普伐他汀限制冠脉粥样硬化研究II(PLAC-II)胆固醇和冠心病复发事件试验(CARE)普伐他汀对缺血性心脏病的
8、长期干预(LIPID)世界卫生组织协作试验(WHO Cooperative Trial)赫尔辛基心脏研究(Helsinki Heart Study,HHS)吉非罗齐冠心病冠脉造影试验(LOCAT)苯扎贝特对年青男性心肌梗死后冠心病进展影响研究(BECAIT)Li H et al.Arterioscler Thromb 1993;13:197-204.Li H et al.Arterioscler Thromb 1993;13:197-204.Navab M et al.J Clin Invest 1991;88:2039-2046.Gu L et al.Mol Cell 1998;2:275-
9、281.*Smith JD et al.Proc Natl Acad Sci U S A 1995;92:8264-8268.Qiao JH et al.Am J Pathol 1997;150:1687-1699.Rajavashisth T et al.J Clin Invest 1998;101:2702-2710.LumenLipidCoreFibrous capShoulderIntimaMediaElasticlaminInternalExternalGalis ZS et al.J Clin Invest 1994;94:2493-2503.对照组高脂组治疗组Moreno PR,
10、et al.Circulation 2002;105:923-927LipidFibroticThin CapThick CapMacrophagesNo MacrophagesEndotheliumBloodMonocyteCirculating LDL“Trapped”LDLSub-endotheliumOxidativestressOxidativestress*Minimallymodified*FullymodifiedPro-atherogenic effect on arterial cellsCytotoxicityMacrophageFoam cellAtherosclero
11、ticlesionHDL,VLDL,LDL,Lp(a)Smooth muscle cellsLDL动脉粥样硬化O2-O2-多不饱和脂肪酸双链断裂 ApoB共轭双烯修改LDL表面结构Witztum,J.L.et al.J.Clin.Invest.1991.88,1785-1792巨噬细胞吸烟运动饮食药物血压Daniel S,et al.Nature Medicine.2002 Nov;8(11):1211-7OX-LDL作用文 献诱导单核细胞绑定粘附到内皮细胞Watson,A.D.et al.J.Biol.Chem.272,13597-13607(1997)仿血小板活化因子(PAF)作用Mara
12、the,G.K.et al.J.Biol.Chem.274,28395-28404(1999)增强组织因子(TF)活性Marathe,G.K.et al.J.Biol.Chem.274,28395-28404(1999)增强巨噬细胞集落刺激因子(M-SCF)基因表达Navab,M.et al.J.Clin.Invest.88,2039-2046(1991)增强单核细胞趋化蛋白-1(MCP-1)基因表达Navab,M.et al.J.Clin.Invest.88,2039-2046(1991)增强血管粘附分子-1(VCSM-1)基因表达Cybulsky,M.I.et al.Science 251
13、,788-791(1991)诱导脂肪合成酶(FAS)介导的细胞凋亡Sata,M.et al.J.Clin.Invest.102,1682-1689(1998)诱导IL-1,IL-8表达Terkeltaub,R.et al.Arterioscler Thromb.14,47-53(1994)抑制一氧化氮NO释放及其保护内皮功能Murohara,T.et al.Am.J.Physiol.267,H2441-H2449(1994)增加平滑肌细胞内胶原蛋白的合成Jimi,S.et al.Atherosclerosis 116,15-26(1995)促进Ca+细胞内流Thorin,E.et al.Ath
14、erosclerosis 114,185-195(1995)激活核转录因子(NF-B)Brand,K.et al.Arterioscler.Thromb.Vasc.Biol.17,1901-1909(1997)诱导基质金属蛋白酶-1(MMP-1)表达 Rajavashisth,T.B.et al.J.Biol.Chem.274,11924-11929(1999)作 用MM-LDLOX-LDL细胞内脂质聚集NoYes与ApoB交连形成共轭双烯NoYes与清道夫受体结合NoYes与LDL-R结合YesNo激活炎性因子YesNo抑制内皮衍生舒张因子(EDRF)NoYes免疫抗原性NoYes细胞毒作用
15、NoYes趋化血浆单核细胞NoYes诱导细胞凋亡NoYes原型LDLMM-LDLOX-LDLLDL氧化修饰程度对慢性炎症的诱导作用细胞毒作用Judith A.et al.Circulation.1995;91:2488-24960.01.02.03.0Gordon T et al.Am J Med 1977;62:707-714.Kannel WB.Am J Cardiol 1983;52:9B12B.Kannel WB.Am J Cardiol 1987;59:80A90A 迄今为止AS的确切机制尚未完全阐明，近年来较一致的认为:多种危险因素 内皮功能紊乱(炎症的启动因子)OX-LDL浸润形
16、成泡沫细胞(关键环节)细胞因子、炎性介质、生物酶 及平滑肌细胞增值迁移 导致动脉壁炎症内皮功能损伤是AS的始动环节泡沫细胞形成AS的早期表现LDL的氧化修饰是泡沫细胞形成的关键环节 血管内皮 平滑肌细胞 单核细胞 淋巴细胞 血小板Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA.1993;269:3015-3023国际工作组,欧洲动脉粥样硬化学会指南,1998+ClCOOCH3CH3CCOOCHCH3CH3ClOCCOOC2H5CH3CH3CCOOHCH3CH3
17、CH2OCH2CH2CH2CH3CH3+LXL/RXR ACAT+OHCH3CH3H3CH3COHOH3CHOOHCH3HH3CHOOHHOCOONaHHH3COOHCH3HH3CH3CHOHH3CHNO*Na+CH3CH3NNHCCH3OCH2CH3Lennernas H et al.Clin Pharmacokinet 1997;32:403423.OCH3CH3OHOHOOOFFOHOHOCH3FOHOHO*Na+OCH3CH3NO*Ca+OO H3COCH3OOHOH3CHHOLovastatinSTATINSBBTGC-IICEFCFCA-I+?COOHCOOH分 类 油 品 饱和脂肪酸（SFA，saturated fatty acid）动物油、棕榈油 单元不饱和脂肪酸（MUFA，mono unsaturated fatty acid）橄榄油 多元不饱和脂肪酸（PUFA，poly unsaturated fatty acid）-3系列 鱼油、苏子油、亚麻仁油-6系列 红花油、向日葵油、月见草油 2O2-O2-O2-S C SHO3(CH3)C3(CH3)COHC(CH3)3C(CH3)3COOH3(CH3)COC(CH3)3OOC(CH3)33(CH3)COO2-Murphy HC et al.Biochemistry 2000;39:9763-970.+.谢谢
