好文档就是一把金锄头!
欢迎来到金锄头文库![会员中心]
电子文档交易市场
安卓APP | ios版本
电子文档交易市场
安卓APP | ios版本

脂代谢与动脉粥样硬化.ppt

136页
  • 卖家[上传人]:新**
  • 文档编号:577766290
  • 上传时间:2024-08-22
  • 文档格式:PPT
  • 文档大小:4.95MB
  • / 136 举报 版权申诉 马上下载
  • 文本预览
  • 下载提示
  • 常见问题
    • Cardiovascular disease is the leading causeof death among adults worldwide (1996)Coronary disease7.2 millionCancer6.3Cerebrovascular disease4.6Acute lower respiratory tract infections3.9Tuberculosis3.0COPD (chronic obstructive pulmonary disease)2.9Diarrhea (including dysentery)2.5Malaria2.1AIDS1.5Hepatitis B1.2 Coronary mortality:alarming worldwide forecasts Atherosclerosis:a multifactorial disease Main risk factors for coronary heart disease Global projections for the diabetes epidemic:1995-2010 Atherosclerosis Arterial wall:structure and function Different stages of atherosclerotic plaquedevelopment Vascular endothelium modificationin atherosclerosis Plaque formation1 — Fatty streak Plaque formation2 — Fibrous cap Plaque formation3 — Lipid core From plaque to thrombosis, key event: plaque rupture Lipid core constitutionActivated macrophages accumulate lipids Lipid core constitutionLDL oxidation Parietal vascular inflammationThe activated macrophage produces inflammatory cytokines Parietal vascular inflammationNFB action in the inflammation process Diabetes and atherosclerosis Tobacco and atherosclerosis Dyslipidemia and atherosclerosis HTN, hemodynamic factor and atheroclerosis How to reduce plaque formationIntervention on risk factors How to reduce the risk of plaque rupture How to reduce the risk of thrombosis ~10% Weight loss = ~30% Visceraladipose tissue loss Characteristics of an unstable plaque Plaque vulnerability factorsIntrinsic factors Modification of extrinsic vulnerability factors Plaque rupture The main releasing factors Classification of lipids and lipoproteins Characteristics of lipoproteins Triglyceride-rich lipoproteins:size, structure and composition Digestion and metabolism of dietary fat HDL metabolism and reverse cholesterol transport Cholesterol efflux and reverse cholesteroltransport is modulated by two receptors Atherogenicity of small dense LDL Size and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particles Size and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particles Apo C-III modulates VLDL Apo C-III in apo B particles is atherogenic Relationship between apo C-III in apo Bcontaining lipoproteins and atherogenicity PROCAM StudyMI-Incidence according to LDL-cholesterol and triglycerides PROCAM StudyCHD risk according to LDL-C and TGincreased TG confers raised CHD risk at all levels of LDL-C HDL:an anti-atherogenic lipoprotein HDL metabolism:5 key genes HDL:apo AI-rich particles Apo A-I protects against atherosclerosis Apo A-II protects against atherosclerosisThe human apo A-II transgenic mouse model Genes and environment in type 2 diabetesand atherosclerosis Pima IndiansThrifty genes Aboriginal Canadians Oji-Cree Obesity, type 2 diabetes, atherosclerosis The Metabolic Syndrome Visceral obesity is associated with a clusterof metabolic abnormalities The atherogenic triad PROCAM Study:MI-Incidence according to LDL-cholesterol and triglycerides 70% of men with CHD had a low HDL ≤44mg/dLFramingham Male Offspring 35-54 Obesity, type 2 diabetes, lipid metabolismThe key role of the transcriptional factors PPARs PPARa discovery elucidatesmechanism of action of fibrates The different PPAR subtypes PPARa:a transcription factor PPARa:transcriptional activation in two stages PPARa:transcriptional activation in two stages Transcriptional activation by PPARa PPARs:regulation of lipoprotein metabolism by PPARa PPARa activators lower small dense LDL An apolipoprotein identified Plasma triglyceride and cholesterol levelsfor human apo A-V transgenic mice Plasma triglyceride and cholesterol levelsfor apo A-V knockout mice Allele frequencies for SNP 3 accordingto plasma triglyceride levels PPARa activators induce apo A-V gene expression PPARa activates human apo A-Vtranscription through two PPREs PPARa: apo A-l, apo A-ll, LPL,ABCA-1 and SR-BI expression PPARa activators induce ABCA-1 gene expressionin human macrophages PPARa activators induce cholesterol effluxfrom human macrophages CLA-1/SR-BI protein may promote cholesterolremoval from peripheral cells CLA-1 expression is regulated by PPARa activatorsin differentiated human macrophages PPARa activators induce cholesterol effluxand reverse cholesterol transport PPARs in the vascular wall Mechanisms of transrepression by PPARa The transcription factor NFB:a key role in the inflammatory response Model of NFB signal pathway inhibition by PPARa activators PPARa activated by fibrates inhibits IL-1binduced expression of COX-2 in SMC Fenofibrate reduces plasma IL-6in patients with CAD Fenofibrate lowers plasma CRPin patients with CAD PPARa activators reduce adhesion moleculeproduction by interfering with NFB PPAR activators reduce endothelin-1 productionby interfering with AP-1 transcription factor PPARa activators inhibit thrombin induced ET-1 secretion in human macro- and microvascular endothelial cells PPARa activators reduce tissue factor production byinterfering with NFB and AP-1 transcription factors PPARa activated by fibrates negativelyregulates fibrinogen-b expression StatinsMolecular mechanisms of actionSREBP feedback control SREBP* regulates the LDL receptorThree-step activation process Common properties of PPARa activatorsand statinsParietal vascular effects Statins and PPARa activators, similar effectsSimilar effector, PPARa? Statins induce PPARa activity Human apo A-I mRNA is inducedby statins in a dose-dependent manner Statins act on apo A-I mRNA expression at the transcriptional levelInhibition by actinomycin D Statin effect on apo A-I synthesisis related to its mode of actionInhibition by mevalonate Statins and PPARa activatorsincrease human apo A-I gene expression Simvastatic acid reduces inducedLPS MMP9 secretion Parietal vascular effects of statins (1)Endothelial cells Parietal vascular effects of statins (2)Monocytes, macrophages PPARa activators act on the main factorsinvolved in the onset of atherosclerosis VA-HIT VA-HIT cont DAIS DAIS cont HHS HHS cont 4S 4S cont CARE CARE cont WOSCOPS WOSCOPS cont LIPID LIPID cont AFCAPS/TexCAPS AFCAPS/TexCAPS cont AVERT AVERT cont HPS HPS cont NCEP guidelines NCEP guidelines cont NCEP guidelines cont NCEP guidelines cont AHA/ACC guidelines ADA guidelines ADA guidelines cont Lipid management for primary prevention of CHD in adults – ILIB recommendations Lipid management for secondary prevention of CHD in adults – ILIB recommendations Lipid management for secondary prevention of CHD in adults with diabetes mellitus – ILIB recommendations Abbreviations list§AS Atherosclerosis§BLBaseline§BMIBody Mass Index§BPBlood Pressure§CABGCoronary Artery Bypass Graft§CADCoronary Artery Disease§CARECholesterol and Recurrent Events§CE Cholesterol Ester§CERPCholesterol Efflux Regulatory Protein§CETP Cholesterol Ester Transfer Protein§CHD Coronary Heart Disease§CHFCongestive Heart Failure§CholCholesterol§COX-2Cyclo-oxygenase-2§CRPC Reactive Protein§CVCardiovascular§CVDCardiovascular Disease§DMDiabetes Mellitus§ECTIM Study Etude CasTemoins de Iífarctus du Myocarde§EREndoplasmic Reticulum§ET-1 Endothelin-1§GE Glycerol Esters§HDL-CHigh-Density Lipoprotein Cholesterol§HL Hepatic Lipase§HTHypertension§ICAM Intercellular Adhesion Molecule§IL Interleukin§LCAT Lecithin Cholesterol Acetyl Transferase§LDL-CLow-Density Lipoprotein Cholesterol§LPL Lipoprotein Lipase§mg/dMilligrams per Day§mg/dLMilligrams per Deciliter§MI Myocardial Infarction§NFBNuclear Factor  B§NSNot Significant§PAI-1Plasminogen Activator Inhibitor Type 1§PlcPlacebo§PPARsPeroxisome Proliferator-Activated Receptors§PROCAMProspective Cardiovascular Munster Study §PPREResponsive Element§PTCAPercutaneous Transluminal Coronary Angiography§RXR Retinoid X Receptor§SigSignificant§SREBPSterol Regulatory Element Binding Protein§TCTotal Cholesterol§TF Tissue Factor§TG Triglyceride§TNF Tumor Necrosis Factor§UAPUnstable Angina Pectoris§VCAM Vascular Cell Adhesion Molecule§vsVersus§WHRWaist Hip Ratio Reference list§Figure 1. WHO press release based on the Director General report, 1997.§Figure 2. Murray CJL and Lopez AD. Evidence-based health policy—lessons from the Global Burden of Disease Study. Science 1996; 274:740–743§Figure 4. Wenger NK. Gender differences in coronary risk factors and risk interventions. In: Atherosclerosis Risk Factors and Treatments, 2nd edition (Ed. Wilson PWF), p214, 1996. §Figure 7. Di Corleto PE, et al. Vascular endothelium. In: Atherosclerosis and Coronary Artery Disease vol. 1, (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, p387, 1996.§Figure 9. Di Corleto, PE, et al. Vascular endothelium. In Atherosclerosis and Coronary Artery Disease, vol. 1. (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, p387, 1996.§Figures 14, 15, 17, 18 and 24. Raines EW, et al. The role of macrophages. In: Atherosclerosis and Coronary Artery Disease (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, p539–551, 1996.§Figures 14, 21, 35 and 36. Falk E, et al. Pathogenesis and plaque disruption. In: Atherosclerosis and Coronary Artery Disease (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, p491–507, 1996.§Figure 26. Aronson D, et al. Diabetes and obesity. In: Atherosclerosis and Coronary Artery Disease (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, p327, 1996.§Figure 27. Stafford RS, et al. Cigarette smoking and atherosclerosis. In: Atherosclerosis and Coronary Artery Disease (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, p303, 1996.§Figure 28. Chisolm GM, et al. Oxidized lipoproteins and atherosclerosis. In: Atherosclerosis and Coronary Artery Disease (Eds. Fuster, Ross, Topor). Lippincott-Raven Publishers, 1996.§Figure 33 and 62. Adapted from Despres JP, Lemieux I and Prud’homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001; 322; 716–720.§Figure 34. Davis MJ et al. Brit Heart J 1993; 69; 377.§Figures 35 and 36. Falk E. Why do plaques rupture? Circulation 1992; 86 (suppl III); 30–42.§Figures 42. Fruchart JC. Physiology of lipids and lipoproteins. Prev Cardiol 1999; 11; 119–125.§Figures 43. Singaraje RR, Fievet C, Castro G, James ER, Hennuyer N, Clee SM, Bissada N, Choy JC, Fruchart JC, McManus BM, Staels B, Hayden MR. Increased ABCA-1 activity protects against atherosclerosis J Clin Invest 2001; 110; 35–42.§Figures 44. Raspe E, Duez H, Gervois P, Fievet C, Fruchart JC, Besnard S, Mariani J, Tedgui A, Staels B. Transcriptional regulation of apolipoprotein C-111 gene expression by the orphan nuclear receptor RORa. J Biol Chem 2001; 276; 2865–2871.§Figures 46. Fruchart JC, Clavey V, Luc G, Dallongeville B, Staels B, Auwerx J. Apolipoprotein C-111 an important player in lipoprotein metabolism. Proc. X11 International Symposium ‘Drug affecting lipid metabolism: risk factors and future directions’. Eds. Gotto M, Paoletti R, Smith LC, et al. Kluwer Academic Publishers, 1996, 631–638.§Figure 47. de Silva HV, Lauer SJ, Wang J et al. Overexpression of human apolipoprotein C-III in transgenic mice results in an accumulation of apolipoprotein B48 remnants that is corrected by excess apolipoprotein E. J Biol Chem 1994; 269; 2324–2335.§Figure 48. Luc G, Fievet C, Arveiler D Evans AE, Bard JM, Cambien F, Fruchart JC, Ducimetiere P. Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. Etude Cas Temoins sur ‘Infarctus du Myocarde’. J Lipid Res 1996; 37; 508–517.§Figure 49 and 50. Sacks FM, Alaupovic P, Moye LA, et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 2000; 102; 1886–1892. Reference list cont§Figures 55. Duverger N, Kruth H, Emmanuel F, Caillaud JM, Viglietta C, Castro G, Tailleux A, Fievet C, Fruchart JC, Houdebine LM, Denefle P. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-1 transgenic rabbits. Circulation 1996; 94; 713–717.§Figure 56. Tailleux A, Bouly M, Luc G, Castro G, Caillard JM, Hennuyer N, Poulain P, Fruchart JC, Duverger N, Denefle P. Decreased susceptibility to diet-induced atherosclerosis in human apolipoprotein A-II transgenic mice. Arterioscler Thromb Vasc Biol 2000; 11; 2453–2458.§Figure 58. Knowler WC, Pettitt DJ and Saad MF, et al. Obesity in the Primas Indians. Its magnitude and relationship with diabetes. Am J Clin Nutr 1991; 53; s1543–1551.§Figure 59. Hegele RA. Genes and environment in type 2 diabetes and atherosclerosis. In: Aboriginal Canadian, Current Atherosclerosis Reports 2002; 3; 216–221.§Figure 63. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998; 279; 1955–1961.§Figure 73. Fruchart JC. Are nuclear factors the ultimate targets of drugs affecting lipid metabolism? Current Atherosclerosis Reports 2000; 2; 353–354.§Figure 75, 76, 77 and 78. Pennancchio LA, Oliver M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rubin EM. An apolipoprotein influencing triglycerides in humans and Mice revealed by comparative sequencing. Science 2001; 294; 169–173.§Figures 82 and 83. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Pineda Torra I, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B. PPARa and PPARg activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA-1 pathway. Nature Medicine 2001; 7; 53–58.§Figure 84 and 85. Chinetti G, Baguidi G, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart JC, Tedgui J, Najib-Fruchart J, Staels B. CLA-1/SR-B1 is expressed in atherosclerosis lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors (PPARs). Circulation 2000; 101; 2411–2417.§Figure 86. Fruchart JC. PPARa activation and HDL metabolism. Am J Cardiol 2001; 88 supp.;24N–29N. §Figure 87, 88, 89, 92, 94 and 94. Staels B, Keonig W, Habib A, Merval R, Lebret M, Pineda Torra I,Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, Tedgui A . Activation of human aortic smooth-muscle cells is inhibited by PPARa but not by PPARg activators. Nature 1998; 393(6686); 790–793. §Figure 90. Delerive Ph, Gervois P, Fruchart JC, Staels B. Induction of IkBa expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-a activators. J Biol Chem 2000; 275/47; 36703–36707.§Figures 95. Delerive P, Fruchart JC and Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 2001; 169; 453–459.§Figure 96 and 97. Delerive P, Martin-Nizard F, Chinetti G, Trottein G, Fruchart JC, Najib J, Duriez P, Staels B. PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Red 1999; 85; 394–402.§Figures 98. Neve BP, Corseaux D, Chinetti G Zawadzki C, Fruchart JC, Duriez P, Staels B, Jude B. PPARa agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation 2001;103; 207-–212.§Figures 99. Gervois P, Vu-Dac R, Kleeman M, Kockx M, Dubois G, Laine B, Kosykh V, Fruchart JC, Kooistra T, Staels B. Negative regulation of human fibrinogen gene expression by PPARa agonists via inhibition of C/EBPb. J Biol Chem 2001; 276; 33471–33477.§Figures 103. Schoonjans K, Peinado-Onsurbe J, Fruchart JC, Tailleux A, Fievet C, Auwerx J. 3-hydroxy-3-methyglutaryl CoA reductase inhibitors reduce serum triglyceride levels through modulation of apolipoprotein C-111 and lipoprotein lipase. FEBS Lett 1999; 452, 160–164.§Figures 105, 106, 107, 108 and 109. Martin G, Duez H, Blanquart C, Berezowski V, Poilain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels, B. Statin induced inhibition of the Rho-signaling pathway activates PPARa and induces HDL apo A-1. J Clin Invest 2001 107 1423–1432. 。

      点击阅读更多内容
      关于金锄头网 - 版权申诉 - 免责声明 - 诚邀英才 - 联系我们
      手机版 | 川公网安备 51140202000112号 | 经营许可证(蜀ICP备13022795号)
      ©2008-2016 by Sichuan Goldhoe Inc. All Rights Reserved.