高级病生第6次课 动脉硬化讲座硕士班.pptVIP

“Chronic inflammatory disorder of intima of large blood vessels characterised by formation of fibrofatty plaques called atheroma”. Hardening of arteries - Arteriosclerosis Lipid metabolism imbalance Classification of lipids and lipoproteins Digestion and metabolism of dietary fat HDL metabolism and reverse cholesterol transport Cholesterol efflux and reverse cholesteroltransport is modulated by two receptors HDL metabolism:5 key genes LDL Classes of Scavenger Receptors Inflammation Immuno-response Why does oxidized LDL become immunogenic? Fragmentation of apo B-100 Oxidation of phospholipids Formation of covalent aldehyde (MDA) and amino acid adducts How Does Immunization With Oxidized LDL Affect Atherosclerosis? Reduced development of atherosclerosis in rabbits (Palinski et al PNAS 1995, Ameli et al ATVB 1996) Reduced development of atherosclerosis in apo E deficient mice (George et al Atherosclerosis 1998, Freigang et al ATVB 1998, Zhou et al ATVB 2001) Is it possible to produce a vaccine against atherosclerosis? What structures in oxidized LDL are recognized by the immune system? Are these immune responses associated with cardiovascular disease in humans? Can protective immune responses be selectively activated by a vaccine? Can antibodies be used directly to treat atherosclerosis? Characterization of epitopes in oxidized LDL by a library of peptide ELISAs 302 peptides, corresponding to the complete amino acid sequence of Apo B-100 Each peptide consists of 20 amino acids with 5 amino acids overlap Modification by malondialdehyde (MDA) Active immunization of apo E null mice with apo B-100 peptide sequences Immunization with 100 mg peptides at 6, 9 and 11 weeks of age using Alum as adjuvant High cholesterol diet at 10 weeks of age Atherosclerosis assessed by Oil Red O staining of the descending aorta at 25 weeks of age Effect of oxidized LDL peptide vaccines on atherosclerosis in mice Effect of immunization with MDA-apoB- 100 peptide 45 on specif