臨床血脂學(xué)與與動(dòng)脈粥樣硬化課件

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;145:227-23

2、8.Rye KA 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-2COSCoAhttp:/ PiCO2acetyl CoAacetyl CoA carboxylaseCOCH2

3、SCoACOOHmalonyl CoACOCH2SACPCOOHCoASHacyl transferasemalonyl acyl carrier proteinACP-SHCO2 -keto-acyl ACP synthaseCOCH2SACPCCH2ORNADPHNADP+COCH2SACPHCCH2ROH -keto-acyl ACPreductaseH2OCOCHSACPCHCH2R -hydroxy-acyl ACPdehydrataseNADPHNADP+COCH2SACPCH2CH2Renoyl ACPreductaseketo-acyl ACPhydroxy-acyl ACPe

4、noyl ACPfatty acyl ACPCH2RCSOACPfatty acyl ACPCH3CH3CH3CH3CH3CH3CellMembraneLiverPeripheraltissuesVLDL, IDL, LDLLDL receptorLCATCETPFCCECETGTGCEHDLHDLFree cholesterol (FC)TriglyceridesCholesterol estersCETP Cholesteryl ester transfer proteinLCATLecithin cholesterol acyltransferaseSR-BIAIC-II C-IEEAI

5、IAIIAII EEhttp:/ Angeles Veterans Study, LAVS)奧斯陸一級(jí)預(yù)防試驗(yàn)(Oslo Primary Prevention Trial)多危險(xiǎn)因素干預(yù)試驗(yàn)(MRFIT)歐洲協(xié)作研究(The European Collaborative Trial)飲食與再梗死試驗(yàn)(DART)手術(shù)控制高脂血癥試驗(yàn)(POSCH)血脂研究臨床中心與CHD一級(jí)預(yù)防試驗(yàn)(Lipid Research Clinics Coronary Primary Prevention Trial) (LRC-CPPT)冠心病干預(yù)研究(Coronary InterventionsStudy, CIS

6、)降低膽固醇與的動(dòng)脈粥樣硬化研究之一(Cholesterol-Lowering Atherosclerosis Study, CLAS-I)降低膽固醇與的動(dòng)脈粥樣硬化研究之二(Cholesterol-Lowering Atherosclerosis Study, CLAS-II)圣托馬斯粥樣硬化消退研究(St Thomas Atherosclerosis Regression Study, STARS)冠心病藥物治療方案(coronary Drug Project, CDP)家族性動(dòng)脈粥樣硬化治療研究(FATS)監(jiān)測動(dòng)脈粥樣硬化消退研究(MARS)無癥狀性頸動(dòng)脈斑塊研究(ACAPS)老年人降膽

7、固醇計(jì)劃(CRISP)加拿大冠狀動(dòng)脈粥樣硬化干預(yù)試驗(yàn)(CCAIT)空軍得州克薩斯冠狀動(dòng)脈粥樣硬化預(yù)防研究(AFCAPS/TexCAPS)北歐辛伐他汀生存研究(4S)多中心抗動(dòng)脈粥樣瘤研究(MAAS)普伐他汀對(duì)冠心病患者冠狀動(dòng)脈粥樣病變消退影響的研究(REGRESS)Kuopio動(dòng)脈粥樣硬化預(yù)防研究(KAPS)西蘇格蘭冠心病預(yù)防研究(WOSCOPS)普伐他汀限制冠狀動(dòng)脈粥樣硬化I(PLAC I)普伐他汀限制冠脈粥樣硬化研究II(PLAC-II)膽固醇和冠心病復(fù)發(fā)事件試驗(yàn)(CARE)普伐他汀對(duì)缺血性心臟病的長期干預(yù)(LIPID)世界衛(wèi)生組織協(xié)作試驗(yàn)(WHO Cooperative Trial)赫爾

8、辛基心臟研究(Helsinki Heart Study, HHS)吉非羅齊冠心病冠脈造影試驗(yàn)(LOCAT)苯扎貝特對(duì)年青男性心肌梗死后冠心病進(jìn)展影響研究(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;2:275-281.*Smith JD et al. Proc Natl Acad Sci U

9、 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. 對(duì)照組高脂組治療組Moreno PR, et al. Circulation 2002;105:923-927

10、LipidFibroticThin CapThick CapMacrophagesNo MacrophagesEndotheliumBloodMonocyteCirculating LDL“Trapped” LDLSub-endotheliumOxidativestressOxidativestress*Minimallymodified* * *FullymodifiedPro-atherogenic effect on arterial cellsCytotoxicityMacrophageFoam cellAtheroscleroticlesionHDL, VLDL, LDL, Lp(a

11、)Smooth muscle cellsLDL動(dòng)脈粥樣硬化O2-O2-多不飽和脂肪酸雙鏈斷裂 ApoB共軛雙烯修改LDL表面結(jié)構(gòu)Witztum, J.L. et al. J. Clin. Invest. 1991. 88, 1785-1792巨噬細(xì)胞吸煙運(yùn)動(dòng)飲食藥物血壓Daniel S, et al. Nature Medicine. 2002 Nov; 8(11):1211-7OX-LDL作用文 獻(xiàn)誘導(dǎo)單核細(xì)胞綁定粘附到內(nèi)皮細(xì)胞Watson, A.D. et al.J.Biol. Chem. 272, 13597-13607 (1997)仿血小板活化因子(PAF)作用Marathe, G.K

12、. et al.J.Biol. Chem. 274, 28395-28404 (1999)增強(qiáng)組織因子(TF)活性Marathe, G.K. et al.J.Biol. Chem. 274, 28395-28404 (1999)增強(qiáng)巨噬細(xì)胞集落刺激因子(M-SCF)基因表達(dá)Navab, M. et al. J. Clin. Invest. 88, 2039-2046 (1991)增強(qiáng)單核細(xì)胞趨化蛋白-1(MCP-1)基因表達(dá)Navab, M. et al. J. Clin. Invest. 88, 2039-2046 (1991)增強(qiáng)血管粘附分子-1(VCSM-1)基因表達(dá)Cybulsky,

13、M.I. et al.Science 251, 788-791(1991)誘導(dǎo)脂肪合成酶(FAS)介導(dǎo)的細(xì)胞凋亡Sata, M. et al.J. Clin. Invest. 102, 1682-1689 (1998)誘導(dǎo)IL-1,IL-8表達(dá)Terkeltaub, R. et al.Arterioscler Thromb. 14, 47-53 (1994)抑制一氧化氮NO釋放及其保護(hù)內(nèi)皮功能Murohara, T. et al.Am. J. Physiol. 267, H2441-H2449 (1994)增加平滑肌細(xì)胞內(nèi)膠原蛋白的合成Jimi, S. et al.Atherosclerosi

14、s 116, 15-26 (1995)促進(jìn)Ca+細(xì)胞內(nèi)流Thorin, E. et al.Atherosclerosis 114, 185-195 (1995)激活核轉(zhuǎn)錄因子(NF-B)Brand, K. et al.Arterioscler. Thromb. Vasc. Biol. 17, 1901-1909 (1997)誘導(dǎo)基質(zhì)金屬蛋白酶-1(MMP-1)表達(dá) Rajavashisth, T.B. et al.J. Biol. Chem. 274, 11924-11929 (1999)作 用MM-LDLOX-LDL細(xì)胞內(nèi)脂質(zhì)聚集NoYes與ApoB交連形成共軛雙烯NoYes與清道夫受體結(jié)合

15、NoYes與LDL-R結(jié)合YesNo激活炎性因子YesNo抑制內(nèi)皮衍生舒張因子(EDRF) NoYes免疫抗原性NoYes細(xì)胞毒作用NoYes趨化血漿單核細(xì)胞NoYes誘導(dǎo)細(xì)胞凋亡NoYes原型LDLMM-LDLOX-LDLLDL氧化修飾程度對(duì)慢性炎癥的誘導(dǎo)作用細(xì)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 19

16、87;59:80A90A 迄今為止AS的確切機(jī)制尚未完全闡明， 近年來較一致的認(rèn)為: 多種危險(xiǎn)因素 內(nèi)皮功能紊亂(炎癥的啟動(dòng)因子) OX-LDL浸潤形成泡沫細(xì)胞(關(guān)鍵環(huán)節(jié)) 細(xì)胞因子、炎性介質(zhì)、生物酶 及平滑肌細(xì)胞增值遷移 導(dǎo)致動(dòng)脈壁炎癥內(nèi)皮功能損傷是AS的始動(dòng)環(huán)節(jié)泡沫細(xì)胞形成AS的早期表現(xiàn)LDL的氧化修飾是泡沫細(xì)胞形成的關(guān)鍵環(huán)節(jié) 血管內(nèi)皮 平滑肌細(xì)胞 單核細(xì)胞 淋巴細(xì)胞 血小板Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 1993;269: 301

17、5-3023國際工作組,歐洲動(dòng)脈粥樣硬化學(xué)會(huì)指南, 1998+ClCOOCH3CH3CCOOCHCH3CH3ClOCCOOC2H5CH3CH3CCOOHCH3CH3CH2OCH2CH2CH2CH3CH3+LXL/RXR ACAT +OHCH3CH3H3CH3COHOH3CHOOHCH3HH3CHOOHHOCOONaHHH3COOHCH3HH3CH3CHOHH3CHNO*Na+CH3CH3NNHCCH3OCH2CH3Lennernas H et al. Clin Pharmacokinet 1997;32:403423.OCH3CH3OHOHOOOFFOHOHOCH3FOHOHO*Na+OCH3CH3NO* Ca+OO H3COCH3OOHOH3CHHOLovastatinSTATINSBBTGC-IICEFCFCA-I+?COOHCOOH分 類 油 品 飽和脂肪酸（SFA，saturated fatty acid