脂代谢与动脉粥样硬化.ppt

Cardiovascular disease is the leading cause of death among adults worldwide (1996),Coronary disease 7.2 million Cancer 6.3 Cerebrovascular disease 4.6 Acute lower respiratory tract infections 3.9 Tuberculosis 3.0 COPD (chronic obstructive pulmonary disease) 2.9 Diarrhea (including dysentery) 2.5 Malaria 2.1 AIDS 1.5 Hepatitis B 1.2,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 plaque development,Vascular endothelium modification in atherosclerosis,Plaque formation 1 Fatty streak,Plaque formation 2 Fibrous cap,Plaque formation 3 Lipid core,From plaque to thrombosis, key event: plaque rupture,Lipid core constitution Activated macrophages accumulate lipids,Lipid core constitution LDL oxidation,Parietal vascular inflammation The activated macrophage produces inflammatory cytokines,Parietal vascular inflammation NFkB action in the inflammation process,Diabetes and atherosclerosis,Tobacco and atherosclerosis,Dyslipidemia and atherosclerosis,HTN, hemodynamic factor and atheroclerosis,How to reduce plaque formation Intervention on risk factors,How to reduce the risk of plaque rupture,How to reduce the risk of thrombosis,10% Weight loss = 30% Visceral adipose tissue loss,Characteristics of an unstable plaque,Plaque vulnerability factors Intrinsic 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 cholesterol transport 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 B containing lipoproteins and atherogenicity,PROCAM Study MI-Incidence according to LDL-cholesterol and triglycerides,PROCAM Study CHD risk according to LDL-C and TG increased 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 atherosclerosis The human apo A-II transgenic mouse model,Genes and environment in type 2 diabetes and atherosclerosis,Pima Indians Thrifty genes,Aboriginal Canadians Oji-Cree,Obesity, type 2 diabetes, atherosclerosis,The Metabolic Syndrome,Visceral obesity is associated with a cluster of 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/dL Framingham Male Offspring 35-54,Obesity, type 2 diabetes, lipid metabolism The key role of the transcriptional factors PPARs,PPARa discovery elucidates mechanism 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 levels for human apo A-V transgenic mice,Plasma triglyceride and cholesterol levels for apo A-V knockout mice,Allele frequencies for SNP 3 according to plasma triglyceride levels,PPARa activators induce apo A-V gene expression,PPARa activates human apo A-V transcription through two PPREs,PPARa: apo A-l, apo A-ll, LPL, ABCA-1 and SR-BI expression,PPARa activators induce ABCA-1 gene expression in human macrophages,PPARa activators induce cholesterol efflux from human macrophages,CLA-1/SR-BI protein may promote cholesterol removal from peripheral cells,CLA-1 expression is regulated by PPARa activators in differentiated human macrophages,PPARa activators induce cholesterol efflux and reverse cholesterol transport,PPARs in the vascular wall,Mechanisms of transrepression by PPARa,The transcription factor NFkB: a key role in the inflammatory response,Model of NFkB signal pathway inhibition by PPARa activators,PPARa activated by fibrates inhibits IL-1b induced expression of COX-2 in SMC,Fenofibrate reduces plasma IL-6 in patients with CAD,Fenofibrate lowers plasma CRP in patients with CAD,PPARa activators reduce adhesion molecule production by interfering with NFkB,PPAR activators reduce endothelin-1 production by 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 by interfering with NFkB and AP-1 transcription factors,PPARa activated by fibrates negatively regulates fibrinogen-b expression,Statins Molecular mechanisms of action SREBP feedback control,SREBP* regulates the LDL receptor Three-step activation process,Common properties of PPARa activators and statins Parietal vascular effects,Statins and PPARa activators, similar effects Similar effector, PPARa?,Statins induce PPARa activity,Human apo A-I mRNA is induced by statins in a dose-dependent manner,Statins act on apo A-I mRNA expression at the transcriptional level Inhibition by actinomycin D,Statin effect on apo A-I synthesis is related to its mode of action Inhibition by mevalonate,Statins and PPARa activators increase human apo A-I gene expression,Simvastatic acid reduces induced LPS MMP9 secretion,Parietal vascular effects of statins (1) Endothelial cells,Parietal vascular effects of statins (2) Monocytes, macrophages,PPARa activators act on the main factors involved 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 BL Baseline BMI Body Mass Index BP Blood Pressure CABG Coronary Artery Bypass Graft CAD Coronary Artery Disease CARE Cholesterol and Recurrent Events CE Cholesterol Ester CERP Cholesterol Efflux Regulatory Protein CETP Cholesterol Ester Transfer Protein CHD Coronary Heart Disease CHF Congestive Heart Failure Chol Cholesterol COX-2 Cyclo-oxygenase-2 CRP C Reactive Protein CV Cardiovascular CVD Cardiovascular Disease DM Diabetes Mellitus ECTIM Study Etude CasTemoins de Ifarctus du Myocarde ER Endoplasmic Reticulum ET-1 Endothelin-1 GE Glycerol Esters HDL-C High-Density Lipoprotein Cholesterol HL Hepatic Lipase HT Hypertension ICAM Intercellular Adhesion Molecule,IL Interleukin LCAT Lecithin Cholesterol Acetyl Transferase LDL-C Low-Density Lipoprotein Cholesterol LPL Lipoprotein Lipase mg/d Milligrams per Day mg/dL Milligrams per Deciliter MI Myocardial Infarction NFkB Nuclear Factor B NS Not Significant PAI-1 Plasminogen Activator Inhibitor Type 1 Plc Placebo PPARs Peroxisome Proliferator-Activated Receptors PROCAM Prospective Cardiovascular Munster Study PPRE Responsive Element PTCA Percutaneous Transluminal Coronary Angiography RXR Retinoid X Receptor Sig Significant SREBP Sterol Regulatory Element Binding Protein TC Total Cholesterol TF Tissue Factor TG Triglyceride TNF Tumor Necrosis Factor UAP Unstable Angina Pectoris VCAM Vascular Cell Adhesion Molecule vs Versus WHR Waist Hip Ratio,Reference list,Figure 1. 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CLA-1/SR-B1 is expressed in atherosclerosis lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors (PPARs). Circulation 2000; 101; 24112417. Figure 86. Fruchart JC. PPARa activation and HDL metabolism. Am J Cardiol 2001; 88 supp.;24N29N. 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); 790793. Figure 90. Delerive Ph, Gervois P, Fruchart JC, Staels B. Induction of IkBa expression as a mechani