Abstract P097: Endothelial Overexpression of LOX-1 Decreases Arterial Thrombosis and TF Expression in Vivo : Role of SIRT-1 and NFκB

Abstract

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 ). 12-week-old male LOX-1TG and wild-type (WT) mice were applied for carotid artery thrombosis model. LOX-1TG mice developed carotid artery thrombosis within a mean occlusion time of 36.96±4.83 min, while WT control mice occluded within a mean time period of 22.75±3.87 min (n=10, P < 0.05). Initial blood flow in carotid artery did not differ between both groups of mice. Decreased occlusion time was in LOX-1TG mice 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 protective role in the arterial thrombosis when expressed at unphysiological levels. Therefore, LOX-1 might represent a novel therapeutic target for atherosclerosis.