Abstract 19248: Endothelial Overexpression of LOX-1 Protects From in vivo Arterial Thrombosis and Modulates Oct-1 and SIRT1 Expression

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 EC, 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. Methods and Results: We generated endothelial-specific LOX-1 transgenic mice using the Tie2 promoter ( LOX-1TG ). 12-wk-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 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. Decreased occlusion time in LOX-1TG mice was further associated with decreased tissue factor expression and surface activity as shown by qPCR and ELISA. Furthermore, LOX-1TG mice showed increased mRNA and protein expression of transcription factor Oct-1 and histone deacetylase SIRT1 in carotid artery, pointing out that Oct-1 and SIRT1 both may be involved in the observed downregulation of tissue factor through its known target NF-kB. Indeed, in vivo knockdown of either Oct-1 or SIRT1 by siRNA further confirmed their role in arterial thrombosis. Conclusions: Thus, our data suggest that LOX-1 plays a protective role in the arterial thrombosis and that both Oct-1 and SIRT1 are involved representing new LOX-1-mediating signaling pathway. Hence, modulation of LOX-1 may represent novel therapeutic options for targeting arterial thrombosis.