期刊
CIRCULATION JOURNAL
卷 80, 期 12, 页码 2541-+出版社
JAPANESE CIRCULATION SOC
DOI: 10.1253/circj.CJ-16-0808
关键词
Atherosclerosis; Developmental endothelial locus-1 (Del-1); LOX-1; Oxidized low-density lipoprotein (LDL)
资金
- Japan Society for the Promotion of Science [JP25670133]
- Grants-in-Aid for Scientific Research [15K01309] Funding Source: KAKEN
Background: 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. Methods and Results: 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 MCP-1 and ICAM-1 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. Conclusions: Del-1 intercepted oxLDL before its receptor binding to reduce atherogenesis.
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