Low density lipoproteins downregulate lysyl oxidase in vascular endothelial cells and the arterial wall.
OBJECTIVE
Hypercholesterolemia induces endothelial dysfunction, a hallmark of the atherosclerotic process, modulating the expression of key genes in vascular endothelial cells.


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 beta-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.
Rodríguez
Cristina
C
Instituto de Investigación Cardiovascular de Barcelona, CSIC-ICCC-Hospital de Sant Pau, Barcelona, Spain.
Raposo
Berta
B
Martínez-González
José
J
Casaní
Laura
L
Badimon
Lina
L
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001158:Arteries / Q000201:enzymology*; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology; D001562:Benzimidazoles / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006937:Hypercholesterolemia / Q000150:complications / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
C110962:5,6-dichlorobenzimidazole; D001562:Benzimidazoles; D008077:Lipoproteins, LDL; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003513:Cycloheximide; D008249:Protein-Lysine 6-Oxidase