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In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish

 Longhou Fang  ;  Simone R. Green  ;  Ji Sun Baek  ;  Sang-Hak Lee  ;  Felix Ellett  ;  Elena Deer  ;  Graham J. Lieschke  ;  Joseph L. Witztum  ;  Sotirios Tsimikas  ;  Yury I. Miller 
 JOURNAL OF CLINICAL INVESTIGATION, Vol.121(12) : 4861-4869, 2011 
Journal Title
Issue Date
Animals ; Animals, Genetically Modified ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Anticholesteremic Agents/therapeutic use ; Blood Vessels/metabolism* ; Cholesterol, Dietary/pharmacokinetics* ; Disease Models, Animal* ; Drug Evaluation, Preclinical ; Epitopes/immunology ; Genes, Reporter ; Green Fluorescent Proteins/analysis ; Green Fluorescent Proteins/genetics ; Humans ; Hydrazines/analysis ; Hypercholesterolemia/drug therapy ; Hypercholesterolemia/metabolism* ; Hypercholesterolemia/therapy ; Immunoglobulin Fab Fragments/genetics ; Lipoproteins, LDL/immunology ; Lipoproteins, LDL/metabolism* ; Macrophages/metabolism ; Macrophages/ultrastructure ; Malondialdehyde/analogs & derivatives* ; Malondialdehyde/immunology ; Malondialdehyde/metabolism ; Microscopy, Confocal/methods* ; Microscopy, Fluorescence/methods* ; Oxidation-Reduction ; Porphobilinogen/analogs & derivatives ; Porphobilinogen/analysis ; Probucol/therapeutic use ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Recombinant Fusion Proteins/therapeutic use ; Single-Chain Antibodies/genetics ; Single-Chain Antibodies/immunology ; Single-Chain Antibodies/therapeutic use ; Temperature ; Veins/metabolism ; Zebrafish/genetics ; Zebrafish/growth & development ; Zebrafish/metabolism* ; Zebrafish Proteins/immunology ; Zebrafish Proteins/metabolism*
Oxidative modification of LDL is an early pathological event in the development of atherosclerosis. Oxidation events such as malondialdehyde (MDA) formation may produce specific, immunogenic epitopes. Indeed, antibodies to MDA-derived epitopes are widely used in atherosclerosis research and have been demonstrated to enable cardiovascular imaging. In this study, we engineered a transgenic zebrafish with temperature-inducible expression of an EGFP-labeled single-chain human monoclonal antibody, IK17, which binds to MDA-LDL, and used optically transparent zebrafish larvae for imaging studies. Feeding a high-cholesterol diet (HCD) supplemented with a red fluorescent lipid marker to the transgenic zebrafish resulted in vascular lipid accumulation, quantified in live animals using confocal microscopy. After heat shock-induced expression of IK17-EGFP, we measured the time course of vascular accumulation of IK17-specific MDA epitopes. Treatment with either an antioxidant or a regression diet resulted in reduced IK17 binding to vascular lesions. Interestingly, homogenates of IK17-EGFP-expressing larvae bound to MDA-LDL and inhibited MDA-LDL binding to macrophages. Moreover, sustained expression of IK17-EGFP effectively prevented HCD-induced lipid accumulation in the vascular wall, suggesting that the antibody itself may have therapeutic effects. Thus, we conclude that HCD-fed zebrafish larvae with conditional expression of EGFP-labeled oxidation-specific antibodies afford an efficient method of testing dietary and/or other therapeutic antioxidant strategies that may ultimately be applied to humans.
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Yonsei Authors
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
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