Abstract 17709: Endothelial Overexpression of LOX-1 Increases Aortic oxLDL Uptake, Induces Endothelial Dysfunction and Plaque Formation in vivo. Role of Oct-1, SIRT-1 and NFκB
Background: The hallmark of the initiation of atherosclerotic lesion is foam cell formation, and oxidized LDL (OxLDL) is believed to play a key role in the initiation of the atherosclerotic process. OxLDL is internalized by several receptors, such as SR-AI/II, SR-BI, CD36, and CD68. OxLDL is also internalized by endothelial cells, but this uptake depends on receptors other than the classic scavenger receptors. In 1997, a lectin-like oxidized LDL receptor-1 (LOX-1, OLR1) was identified in bovine aortic endothelial cells. LOX-1 is a type II membrane glycoprotein with an apparent molecular weight of 50 kDa. It has a C-terminal extracellular C-type lectin-like domain. This lectin-like domain is essential for binding to OxLDL. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO, which may trigger the onset of cardiovascular events or accelerate the development of atherosclerosis.
Methods and Results: We generated endothelial-specific LOX-1 transgenic mice using the Tie2 promoter (LOX-1TG). In endothelial cells, but not macrophages, LOX-1TGmice exhibited enhanced oxLDL uptake. 6-week-old male LOX-1TG and wild-type (WT) mice were fed a high cholesterol diet for 30 weeks. In LOX-1TG vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression, macrophage accumulation and aortic fatty streaks were increased, while eNOS phosphorylation and endothelial function were reduced. In endothelial cells of LOX-1TG mice, reactive oxygen species were increased and the transcription factors NF-κB and Oct-1 activated. In atherosclerotic LOX-1TG/ApoE−/− mice, high cholesterol diet increased VCAM-1 expression, number of macrophages, T-cells as well as plaque size.
Conclusions: Thus, our data suggest that LOX-1 plays a critical role in the development of atherosclerosis when expressed at unphysiological levels. Therefore, LOX-1 might represent a novel therapeutic target for atherosclerosis.
- © 2010 by American Heart Association, Inc.