Abstract 439: Endothelial-specific Overexpression Of Lox-1 Leads To An Increased Atherosclerosis In Mouse
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-To obtain transgenic mice with LOX-1 overexpressed specifically in endothelial cells, we used a murine tyrosine kinase receptor Tie2 promoter. In order to evaluate the tissue distribution of the LOX-1 transgenic expression a quantitative real time PCR was performed. The overexpression of LOX-1 in terms of messenger RNA was confirmed at the protein level by Western blot analysis with anti-LOX-1 antibody. The endothelial-specific overexpression of LOX-1 was confirmed by immunohistochemistry in aortas of transgenic mice. To investigate the effect of LOX-1 overexpression on development of atherosclerosis, 6 week-old LOX-1 transgenic and corresponding WT mice were put on a high fat diet for 30 weeks. The quantification of plaque areas in cross sections of isolated aortas after Oil Red-O staining showed significantly enhanced levels of atherosclerosis in LOX-1 vs WT mice (1342±168.5 vs 709.5±155.5, n=4, p<0.05).
Conclusions-Thus, this observation suggests that LOX-1 plays a critical role in the development of atherosclerosis when expressed at unphysiological levels. Such LOX-1-associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 might represent a potential therapeutic target in future.