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

Research output: Contribution to journalArticle

56 Scopus citations

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 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 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.

Original languageEnglish (US)
Pages (from-to)4861-4869
Number of pages9
JournalJournal of Clinical Investigation
Volume121
Issue number12
DOIs
StatePublished - Dec 1 2011

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish'. Together they form a unique fingerprint.

Cite this