Leiden University Scholarly Publications

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Verwilligen, R.A.F.; Dijke, A. van; Hoekstra, M.; Bussmann, J.; Eck, M. van (2019)

The role of endothelial and macrophage scavenger receptor stabilin 1 and 2 in early atherosclerosis development in zebrafish

Article / Letter to editor
Atherosclerosis, the main underlying cause of cardiovascular disease and related morbidities, is a multifactorial disease in which liver endothelial cells and macrophages have shown to play an important role. Recently, it has been demonstrated that oxidized phospholipids in oxidized LDL (oxLDL) are pro-inflammatory and pro-atherogenic in hypercholesterolaemic mice. Multiple scavenger receptors are known for oxLDL. They form a superfamily of membrane bound receptors that bind and internalize different types of ligands including other modified lipoproteins, endogenous proteins and pathogens. Several studies, including a microarray study of our research group, have already identified scavenger receptors stabilin-1 and -2 (STAB1 and STAB2) as a risk factor for atherosclerosis, and therefore as potential targets for treatment. An upcoming and powerful model organism to study early atherogenesis and that allows non-invasive cell tracking studies is the zebrafish. Recent studies have...Show more

Atherosclerosis, the main underlying cause of cardiovascular disease and related morbidities, is a multifactorial disease in which liver endothelial cells and macrophages have shown to play an important role. Recently, it has been demonstrated that oxidized phospholipids in oxidized LDL (oxLDL) are pro-inflammatory and pro-atherogenic in hypercholesterolaemic mice. Multiple scavenger receptors are known for oxLDL. They form a superfamily of membrane bound receptors that bind and internalize different types of ligands including other modified lipoproteins, endogenous proteins and pathogens. Several studies, including a microarray study of our research group, have already identified scavenger receptors stabilin-1 and -2 (STAB1 and STAB2) as a risk factor for atherosclerosis, and therefore as potential targets for treatment. An upcoming and powerful model organism to study early atherogenesis and that allows non-invasive cell tracking studies is the zebrafish. Recent studies have demonstrated the possibility to induce (early) atherosclerosis in zebrafish.

We have used Crispr/Cas9 mutagenesis to generate zebrafish stab1 and stab2 mutants.

Our results show that oxLDL clearance by zebrafish scavenger endothelial cells (homologous to liver sinusoidal endothelial cells) is diminished in stab2 zebrafish mutants and is absent in stab1/2 double mutants. In stabilin mutants, macrophage oxLDL uptake is increased, suggesting a protective role for stabilins in foam cell formation.

To study this further, we are currently performing an atherosclerosis study to examine foam cell formation and vascular lipid accumulation in stabilin mutant zebrafish.

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All authors
Verwilligen, R.A.F.; Dijke, A. van; Hoekstra, M.; Bussmann, J.; Eck, M. van
Date
2019-08-31
Volume
287
Pages
E101 - E102
DOI
doi:10.1016/j.atherosclerosis.2019.06.295