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1 Department of medicine, New York Medical College, Valhalla, NY, USA
2 Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan
* To whom correspondence should be addressed. E-mail: michael_goligorsky{at}mymc.edu.
Endothelial cell dysfunction (ECD) is emerging as a common denominator for diverse cardiovascular abnormalities associated with inhibition of endothelial nitric oxide (NO) synthase (eNOS). Elevated levels of asymmetric dimethylarginine (ADMA), a potent eNOS inhibitor, are common in renal failure, and may contribute to ECD. Through DNA microarray screening of genes modulated in HUVEC by NG-Nitro-L-arginine-methyl ester (LNAME), we found 1.8-fold increase in LOX-1 expression. LOX-1 is a major endothelial receptor for OxLDL, and assumed to play a role in initiation and progression of atherosclerosis. Here, we confirmed the upregulation of LOX-1 mRNA and protein level by quantitative RT-PCR and Western analysis. Increased expression of LOX-1 was associated with accumulation of DiI-labeled OxLDL (DiI-OxLDL), in ADMA and LNAME-pretreated HUVEC. To evaluate the contribution of LOX-1 in ADMA-induced accumulation of OxLDL by HUVEC we used competitive receptor inhibitor, soluble LOX-1. Treatment of HUVEC with soluble LOX-1 was associated with approximately 2-3-fold inhibition of DiI-OxLDL uptake in LNAME or ADMA-treated HUVEC. In conclusion, ADMA or LNAME-induced NO deficiency leads to the increased expression of LOX-1 mRNA and protein in HUVEC, which in turn results in the accumulation of OxLDL. Competition with LOX-1 soluble extracellular domain, reduces OxLDL accumulation. In summary, elevated ADMA levels, i.e. in patients with renal failure, may be responsible for endothelial accumulation of OxLDL via upregulated LOX-1 receptor, thus contributing to endothelial lipidosis and dysfunction.
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