on August 15, 2002
Published online before print August 15, 2002, doi: 10.1161/01.ATV.0000033818.21748.99
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Submitted on May 30, 2002
Accepted on July 16, 2002
Low Density Lipoproteins Downregulate Lysyl Oxidase in Vascular Endothelial Cells and the Arterial Wall
Cristina Rodríguez ;
From the Instituto de Investigación Cardiovascular de Barcelona, CSIC-ICCC-Hospital de Sant Pau, Barcelona, Spain.
* To whom correspondence should be addressed. E-mail: lbmucv{at}cid.csic.es.
Objective—Hypercholesterolemia induces endothelial dysfunction, a hallmark of the atherosclerotic process, modulating the expression of key genes in vascular endothelial cells.
Methods and Results—By differential display analysis, we have studied the effect of high concentrations of native low density lipoprotein (LDL) on endothelial gene expression. mRNA levels of lysyl oxidase (LOX), an enzyme involved in collagen and elastin cross-linking, were downregulated by LDL treatment in endothelial cells in a dose- and time-dependent manner (80% of inhibition by 180 mg/dL LDL for 24 hours). This reduction of LOX expression was associated with a decrease in LOX activity (40% and 54% of inhibition after 24 and 48 hours of LDL treatment, respectively). LOX mRNA half-life was not modified by LDL, but transcriptional inhibition blocked the effect of LDL. Inhibition of LOX activity by either LDL or ß-aminopropionitrile, an inhibitor of LOX, increased endothelial permeability (192±0.19- and 3.37±0.74-fold, respectively). Interestingly, a reduction in LOX expression (3.5-fold) was observed in vivo in the vascular wall of hypercholesterolemic pigs.
Conclusions—These findings suggest that LDL downregulation of LOX could contribute to the endothelial dysfunction caused by hypercholesterolemia, thus contributing to atherosclerotic plaque formation.
Key words: endothelial cells • low density lipoproteins • lysyl oxidase • vascular permeability • hypercholesterolemia
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