Developmental Endothelial Locus-1 (Del-1) Inhibits Oxidized Low-Density Lipoprotein Activity by Direct Binding, and Its Overexpression Attenuates Atherogenesis in Mice

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Abstract

<p><b><i>Background:</i></b>Modified low-density lipoprotein (LDL) binding to scavenger receptors has been implicated in atherosclerosis. It is hypothesized that a third molecule may affect modified LDL binding, therefore, this study focuses on the soluble endogenous protein, developmental endothelial locus-1 (Del-1), as an inhibitor of oxidized LDL (oxLDL) interactions.</p><p><b><i>Methods and Results:</i></b>Del-1 preferentially bound oxLDL over native LDL in a cell-free binding assay. Del-1 also inhibited DiI-labeled oxLDL uptake by scavenger receptors irrespective of the receptor type (LOX-1, SR-AI, CD36, or SR-BI) expressed in COS-7 cells, and independent of cell type (human coronary artery endothelial cells (HCAECs) or THP-1-derived macrophages). Furthermore, Del-1 suppressed oxLDL-induced<i>MCP-1</i>and<i>ICAM-1</i>expression and endothelin-1 secretion in HCAECs. Then, male Del-1 transgenic (Del-1Tg) and wild-type mice (WT) mice were established and fed a Paigen diet for 20 weeks from the age of 24 weeks. While plasma lipid concentrations did not differ between WT and Del-1Tg mice, plasma LOX-1-ligand activity was significantly lower in Del-1Tg than in WT mice. Moreover, lipid accumulation in aortic roots was significantly less in the Del-1Tg mice, evaluated with Oil red-O. Taken together, Del-1 appears to block the activity of oxLDL pharmacologically by direct binding in vitro, and attenuates atherogenesis in vivo, although its role in physiological settings are yet to be resolved.</p><p><b><i>Conclusions:</i></b>Del-1 intercepted oxLDL before its receptor binding to reduce atherogenesis. (<i>Circ J</i> 2016; <b>80:</b> 2541–2549)</p>

Journal

  • Circulation Journal

    Circulation Journal 80(12), 2541-2549, 2016

    The Japanese Circulation Society

Codes

  • NII Article ID (NAID)
    130005284982
  • NII NACSIS-CAT ID (NCID)
    AA11591968
  • Text Lang
    ENG
  • ISSN
    1346-9843
  • NDL Article ID
    027742934
  • NDL Call No.
    Z54-B860
  • Data Source
    NDL  J-STAGE 
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