The nitric oxide synthase family of proteins is the unique class of mammalian enzymes that metabolizes L-arginine to form nitric oxide (NO). The atherogenic action of low-density lipoproteins (LDL) may be mediated, in part, by its effects on endothelial-derived nitric oxide. To determine whether native LDL (nLDL), at atherogenic concentrations, are capable of modulating NO synthase expression, we treated human umbilical vein endothelial cells with increasing concentrations of human nLDL (0Ϫ240 mg cholesterol/dl) for various time periods (2Ϫ48 h). Northern and western blot analyses indicate that both endothelial NO-synthase mRNA and protein are down-regulated by atherogenic concentrations of nLDL (180 and 240 mg cholesterol/dl) after 48 h of incubation. Cycloheximide and actinomycin D experiments suggest that this down-regulation operates at a transcriptional level. Additionally, treatment of the cells with high-density lipoproteins, at human physiological concentrations (45 mg cholesterol/dl), does not appear to alter the expression of endothelial NO synthase which seems to indicate that nLDL affect the gene transcription rate by a specific and concentration-dependent mechanism. These findings may have important implications because they provide a novel mechanism by which hypercholesterolemia induces early changes on endothelial cells that could have pathophysiological significance in the atherosclerotic process.Keywords : endothelial cells; human umbilical vein endothelial cells; hypercholesterolemia ; low-density lipoprotein; nitric oxide.The endothelium regulates vascular tone by producing pros-On the other hand, hypercholesterolemia is generally associated with an increase in low-density lipoprotein (LDL), which are the tacyclin, nitric oxide (NO) and endothelin, among other vasoactive compounds, in response to several stimuli [1]. Alterations major carriers of cholesterol in the blood. High LDL levels are a known risk factor for the development of atherosclerosis but in endothelial function and related processes are known to be involved in the pathogenesis of many cardiovascular diseases, the mechanisms by which LDL acts and if there is a relationship with NOS regulation is uncertain. It has been reported that LDL including hypertension and atherosclerosis [2].NO, a potent vasodilator, is also released by other cell types: enhance prostacyclin production [6], endocytic activity [7], permeability [8], recruitment of mononuclear cells [9] and synthesis smooth muscle cells, neurons, macrophages and hepatocytes. NO is generated by conversion of L-arginine to L-citrulline by of adhesion molecules [10] in endothelial cells. These findings are important since some of them participate in the atherogenic enzymatic action of NO synthases (NOS). Three isoforms of process and can be inhibited by NO. However, the role of NO NOS have been cloned and characterized: two Ca 2ϩ /calmodulinon endothelial dysfunction associated with hypercholesterolemia dependent isoforms, constitutively expressed in brain and endoor atheroscl...

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