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Slide 1 - 負電性低密度脂蛋白L5與心血管疾病Electronegative Low-Density Lipoprotein and Atherosclerosis Chao-yuh Yang, Ph.D. 楊朝諭 教授 美國貝勒醫學院醫學系及生化系 中國醫藥大學附設醫院, L5研究中心 Academy BioMedical Company
Slide 2 - Atherosclerosis and low-density lipoproteins Atherosclerosis is the leading cause of death in the western country. Atherosclerosis causes significant morbidity and mortality, and associates with enormous economic impact. Increased levels of low-density lipoproteins (LDLs) are associated with increased risk for development of atherosclerosis.
Slide 3 - 1983 Brown and Goldstein et. al reported in New Engl. J. Med: Defective lipoprotein receptors and atherosclerosis. 1985 Brown and Goldstein et. al reported structure for lipoprotein receptors in Science and reported receptor-mediated endocytosis: concepts emerging from the LDL receptor system in Ann. Rev. Cell Biol..
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Slide 5 - ApoB-100 structure in LDL
Slide 6 - ApoB-100 Structure in LDL
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Slide 8 - Steps in atherogenesis
Slide 9 - Stages of atherosclerosis
Slide 10 - Pathologic processes leading to the development of an atherosclerotic plaque
Slide 11 - The three layers of the arterial wall
Slide 12 - Atherosclerosis Heart disease begins when cholesterol, fatty material, andcalcium build up in the arteries, a process known as atherosclerosis.
Slide 13 - HPLC of Cu ox-apoB tryptic peptides
Slide 14 - Electrospray-MS of Cu ox-peptide
Slide 15 - Purified Cu ox-peptides
Slide 16 - Location of Cu ox AA residues on LDL
Slide 17 - Summary ----in vitro ox-LDL Copper ox-LDL results in a) formation of carbonyl group at the Trp residues of apoB-100, b) formation of sulfonic acid, c) formation of HNE-His adducts Exposure of LDL to HOCl or MPO in vitro generates DNPH-reactive sites on the apoprotein (Cys, Trp, Lys) Oxidation of LDL by MPO is remarkably more selective than is oxidation by HOCl in free solution, suggesting the formation of some form of enzyme-substrate complex between MPO and LDL
Slide 18 - Conclusion ---- in vitro ox-LDL Different mechanisms of LDL oxidation can be distinguished by specific characteristic products of oxidation of the apoprotein Most of the modified residues identified so far are incorporated in tryptic peptides shown to reside on the surface of the LDL particle
Slide 19 - Oxidative Modified LDL In vitro Metal-catalyzed oxidation: copper- or iron-oxidation HOCl-mediated oxidation Enzyme-mediated oxidation: myeloperoxidase, lipoxygenases d. Reaction of LDL with lipid-derived aldehydes, e. Cell-mediated oxidative modification In vivo Circulating LDL Atheroma LDL
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Slide 25 - inhibits EC proliferation induces EC apoptosis induces EC expression of adhesion molecules induces monocyte-EC adhesion induces VSMC proliferation inhibits EPC differentiation Circulation 2003; ATVB 2003; Curr Opin Lipidol 2004; Curr Vasc Pharmacol 2004; Atherosclerosis 2007-1, 2007-2; Endocrinology 2007; JLR 2004, 2007, 2008; Diabetes 2008; Circ Res 2006, 2008, 2009-1, 2009-2 What does L5 do to us?
Slide 26 - Relation of cholesterol to coronary death
Slide 27 - LDL-C and HDL-C impact on CHD risk
Slide 28 - Risk ratios for CHD of total cholesterol and HDL cholesterol
Slide 29 - Categories of Risk Factors
Slide 30 - Major Risk Factors (Exclusive of LDL Cholesterol)
Slide 31 - Life-Habit Risk Factors
Slide 32 - Emerging Risk Factors
Slide 33 - LDL Cholesterol (mg/dL) Lipid and Lipoprotein Level Related to health condition
Slide 34 - Total Cholesterol (mg/dL) Lipid and Lipoprotein Level Related to health condition HDL Cholesterol (mg/dL)
Slide 35 - Serum Triglycerides Lipid and Lipoprotein Level Related to health condition
Slide 36 - Causes of Low HDL Cholesterol (<40 mg / dL)
Slide 37 - Causes of Elevated Triglycerides (> 150 md/dL)
Slide 38 - Therapeutic Lifestyle Changes in LDL-Lowering Therapy
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Slide 40 - Cholesterol content (mg/3 oz, 85 g) and total fat content (g/3 oz) of lean meats and organs (cooked)
Slide 41 - Cholesterol content (mg/3 oz) and total fat content (g/3 oz) of poultry (cooked)
Slide 42 - Cholesterol content (mg/3 oz) and total fat content (g/3 oz) of fish and shellfish (cooked)
Slide 43 - Cholesterol content (mg/3 oz) and total fat content (g/3 oz) of eggs and dairy products (cooked)
Slide 44 - Components of nutritionally balanced cholesterol-lowering diet
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Slide 51 - Thank you for your attention