In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish. Academic Article uri icon

Overview

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 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.

authors

  • Fang, Longhou
  • Green, Simone R
  • Baek, Ji Sun
  • Lee, Sang-Hak
  • Ellett, Felix
  • Deer, Elena
  • Lieschke, Graham J
  • Witztum, Joseph L
  • Tsimikas, Sotirios
  • Miller, Yury I

publication date

  • November 21, 2011

Research

keywords

  • Blood Vessels
  • Cholesterol, Dietary
  • Disease Models, Animal
  • Hypercholesterolemia
  • Lipoproteins, LDL
  • Malondialdehyde
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Zebrafish
  • Zebrafish Proteins

Identity

PubMed Central ID

  • PMC3225997

Scopus Document Identifier

  • 84055199892

Digital Object Identifier (DOI)

  • 10.1016/0022-1759(85)90044-4

PubMed ID

  • 22105168

Additional Document Info

volume

  • 121

issue

  • 12