In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish
- Fang, LH; Green, SR; Baek, JS; Lee, SH; Ellett, F; Deer, E; Lieschke, GJ; Witztum, JL; Tsimikas, S; Miller, YI;
Publication Year 2011-12, Volume 121, Issue #12, Page 4861-4869
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Publication Type
- Journal Article
- 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.
- AMER SOC CLINICAL INVESTIGATION INC
- OXIDATION-SPECIFIC EPITOPES; LOW-DENSITY-LIPOPROTEIN; ATHEROSCLEROTIC LESIONS; LDL; ANTIBODIES; PROGRESSION; PROTEIN; IMMUNIZATION; CHOLESTEROL; MACROPHAGES
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2011-12-01 12:00:00Last Modified: 0001-01-01 12:00:00