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1 Department of Medicine and Pathology, 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}nymc.edu.
Intimal infiltration by monocytes and accumulation of lipids represent a critical step in the formation of fatty streaks during atherogenesis. Since elevated plasma levels of asymmetric dimethylarginine (ADMA), a potent NOS inhibitor, are prevalent in diverse cardiovascular diseases, the goal of this study was to examine the contribution of NO deficiency to macrophage lipid accumulation. Inhibition of NO synthesis in PMA-primed HL-60 cells resulted in a 2-fold increase in expression of the receptor for oxidized LDL (OxLDL), lectinlike OxLDL receptor (LOX-1). Blockade of iNOS in activated macrophages resulted in DiIOxLDL accumulation and imparted macrophages with a foamy appearance, as detected with oil red O lipid staining. ADMA (15 µM) or nitro-L-arginine-methyl ester (LNAME) (300 µM), both concentrations suppressing iNOS activity, increased oil-red staining 1.9- and 2.8-fold, respectively. Macrophages treated with ADMA or LNAME showed 2.4-fold increased accumulation of DiI-OxLDL. To examine the role of LOX-1 in this process, we used small interfering RNA (siRNA) duplexes-mediated LOX-1 gene silencing. LOX-1 expression was suppressed 2-fold with siRNA by Western blot analysis. This suppression was associated with a 2-4-fold decrease in DiI-OxLDL uptake by fluorescence microscopy and decreased oil red O staining by activated macrophages. In conclusion, accumulation of competitive inhibitors of nitric oxide synthase, ADMA, in patients with chronic renal failure, may be responsible for upregulation of LOX-1 receptor and increased OxLDL uptake, thus contributing to lipidosis and foam cell formation. The data illustrate an additional non-endothelial mode of antiatherogenic action of NO: prevention of LOX-1 induction and lipid accumulation by macrophages.
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