Emerging applications for zebrafish as a model organism to study oxidative mechanisms and their roles in inflammation and vascular accumulation of oxidized lipids

With the advent of genetic engineering, zebrafish (Danio rerio) were recognized as an attractive model organism to study many biological processes. Remarkably, the small size and optical transparency of zebrafish larvae enable high-resolution imaging of live animals. Zebrafish respond to various environmental and pathological factors with robust oxidative stress. In this article, we provide an overview of the molecular mechanisms involved in oxidative stress and antioxidant response in zebrafish. Existing applications of genetically encoded fluorescent sensors allow imaging, in real time, of the production of H2O2 and studying its involvement in inflammatory responses, as well as activation of the oxidation-sensitive transcription factors HIF and NRF2. Oxidative stress, combined with hyperlipidemia, leads to oxidation of lipoproteins, the process that contributes significantly to the development of atherosclerosis in humans. Recent work found that feeding zebrafish a high-cholesterol diet results in hypercholesterolemia, vascular lipid accumulation, and extreme lipoprotein oxidation. Generation of a transgenic zebrafish expressing a green fluorescent protein-tagged human antibody to malondialdehyde (MDA)-modified LDL makes possible the in vivo visualization of MDA epitopes in the vascular wall and testing of the efficacy of antioxidants and dietary interventions. Thus, using zebrafish as a model organism provides important advantages in studying the roles of reactive oxygen species and lipid oxidation in basic biologic and pathologic processes.

Graphical AbstractFigure optionsDownload high-quality image (420 K)Download as PowerPoint slideHighlights
► Zebrafish respond with robust oxidative stress to many pathological stimuli.
► Genetically encoded reporters enable monitoring of H2O2 and HIF and NRF2 activities.
► Feeding zebrafish a high-cholesterol diet leads to excessive lipoprotein oxidation.
► Transgenic zebrafish with green fluorescent protein-tagged antibody enable imaging of oxidized lipids.
► Fluorescent reporter zebrafish provide methods for in vivo antioxidant screening.