Abstract 16142: Identification of Endogenous Anti-Atherogenic Protein Which Blocks the Interaction Between Oxidized LDL and Its Receptors
Background: It has been generally understood that oxidized LDL (oxLDL) is one of the causes of atherosclerosis. Through binding to its various receptors, oxLDL induces dysfunction in endothelium, causing inflammation and lipid accumulation, and subsequent foam cell formation therein. Although a considerable number of studies have been reported on characterization oxLDL receptors, there have been no reports on endogenous inhibitors that block the interaction between oxLDL and its receptors, despite their potential importance.
Aim: Here, we hypothesized that an endothelium-derived secreting protein Del-1 (developmental endothelial locus-1) might work as such an endogenous inhibitor of oxLDL.
Methods and Results: In a cell-free assay we found that Del-1 selectively bound to oxLDL but not to native LDL. Del-1 inhibited the uptake of DiI-labeled oxLDL (DiI-oxLDL) by LOX-1, but did not inhibit the uptake of DiI-labeled native LDL by LDL receptor expressed in COS-7 cells. Del-1 also inhibited DiI-oxLDL uptake by other oxLDL receptors, such as SR-A, CD36, and SR-BI. We also found that Del-1 inhibited DiI-oxLDL uptake by cultured human umbilical vein endothelial cells (HUVEC) and THP-1-deribed macrophages. Furthermore, Del-1 suppressed oxLDL-dependent signal transduction in LOX-1 expressing CHO cells and in HUVEC. Del-1 also suppressed oxLDL-induced secretion of endothelin-1 in HUVEC. To examine in vivo effects of Del-1 on atherogenesis, we established Del-1 transgenic mice (Del-1Tg), and fed high-fat diet to male Del-1Tg and wild-type mice (WT) (n=6 each) for 20 weeks from the age of 24 weeks. Plasma oxLDL activity was significantly decreased in Del-1Tg compared with WT mice (13.3±4.3 vs. 106.2±20.1 ng/ml, P<0.05), while other lipid parameters except triglycerides were not different. Plasma tryglyceride concentration in Del-1Tg was slightly lower than that in WT. Concomitantly, Oil red O-positive atheromatous area at aortic roots dramatically decreased in Del-l Tg compared with WT (3.1±1.4 vs. 17.7±2.0 % of aortic roots area, P<0.001).
Conclusions: Thus, we demonstrated, for the first time, the existence of an endogenous protein which blocked oxLDL action by directly binding to oxLDL in vitro and attenuated atherogenesis in vivo at least in mice.
- © 2013 by American Heart Association, Inc.