In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish
Details
Publication Year 2011-12, Volume 121, Issue #12, Page 4861-4869
Journal Title
JOURNAL OF CLINICAL INVESTIGATION
Publication Type
Journal Article
Abstract
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 enalb Le 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 MDALDL, 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.
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Keywords
OXIDATION-SPECIFIC EPITOPES; LOW-DENSITY-LIPOPROTEIN; ATHEROSCLEROTIC LESIONS; LDL; ANTIBODIES; PROGRESSION; PROTEIN; IMMUNIZATION; CHOLESTEROL; MACROPHAGES
Publisher's Version
https://doi.org/10.1172/JCI57755
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2011-12-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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