Atherosclerosis and the immune system - Expanding beyond inflammation24Endothelial overexpression of LOX-1 protects from in vivo arterial thrombosis and modulates TF expression

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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 36.96n ± 4.83 min, while WT control mice occluded within a mean time period of 22.75n ± 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 in LOX-1TG mice was further associated with decreased tissue factor expression and surface activity as shown by RT PCR and ELISA. Furthermore, LOX-1TG mice showed increased mRNA expression of histone deacetylase SIRT1 in carotid artery, pointing out that SIRT1 may be involved in the observed downregulation of tissue factor through its known target transcription factor NF-kB.

Conclusions

Thus, our data suggest that LOX-1 plays a protective role in the arterial thrombosis and that SIRT1 may be involved. Hence, modulation of LOX-1 may represent novel therapeutic options for targeting arterial thrombosis.

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