An endogenous oxidized LDL inhibitor Del-1

An endogenous oxidized LDL inhibitor Del-1

Akemi Kakino, Yoshiko Fujita, Tomohide Takaya, Shin Iwamoto, Tatsuya Sawamura.

Department of Vascular Physiology, National Cerebral and Cardiovascular Center, Osaka, Japan.

International Symposium on Atherosclerosis 2012 (Sydney, Australia), 2012/03/27 (Poster).

Abstract

Oxidized LDL (oxLDL) is implicated in atherogenesis through receptor-mediated action which causes vascular cell dysfunction leading to inflammatory responses and lipid accumulation resulting in foam cell formation. Although a huge number of studies have been reported on characterization oxLDL receptors, there have been no reports on endogenous inhibitors for the interaction between oxLDL and its receptors, despite their potential importance. Here, we have identified one such endogenous inhibitor for the first time, which was originally described as an endothelium-derived secreted protein Del-1 (developmental endothelial locus-1). We found that Del-1 potently inhibited DiI-labeled oxLDL (DiI-oxLDL) binding to oxLDL receptors, LOX-1 and SR-A, expressed in COS-7 cells in a dose-dependent manner. Del-1 also inhibited DiI-oxLDL uptake by cultured human umbilical vein endothelial cells (HUVECs), and THP-1 cells differentiated into macrophages. The inhibitory action of Del-1 was based on the Del-1 binding to oxLDL. Del-1 selectively bound to oxLDL but not to native LDL immobilized on a plate in a cell-free assay. Furthermore, Del-1 inhibited DiI-oxLDL uptake by LOX-1, but did not inhibit DiI-labeled native LDL uptake by LDL receptor expressed in COS-7 cells. In addition, we demonstrated that Del-1 suppressed the activation of p42/44 MAP kinase by oxLDL in HUVECs. Thus, Del-1 is an endogenous factor that protects cells from oxLDL-induced endothelial dysfunction, by interfering atherogenic oxLDL binding to its receptors.