© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Gene expression and intracellular pathways involved in endothelial dysfunction induced by VLDL and oxidised VLDL
aDepartment of Pharmacological Sciences, University of Milan, Milan, Italy
bKing Gustaf V Research Institute, Department of Medicine, Karolinska Hospital M1, Karolinska Institute, Stockholm 171 76, Sweden
cCentro per lo Studio e la Prevenzione delle Vasculopatie Periferiche, Ospedale Bassini, Cinisello Balsamo, Italy
per.eriksson{at}medks.ki.se
* Corresponding author. Tel.: +46-8-5177-3202; fax: +46-8-311-298.
Objectives: The molecular mechanisms underlying the relationship between elevated plasma concentrations of triglyceride-rich lipoproteins and coronary artery disease remain uncertain. In the present work, we investigated the gene expression pattern and intracellular pathways in human endothelial cells incubated with very low density lipoproteins (VLDL). Moreover, as VLDL can enter the arterial wall and undergo oxidative modification, we compared the VLDL-induced expression pattern with the one of oxidised VLDL (Ox-VLDL). Methods: Total RNA from endothelial cells incubated with 75 µg/ml VLDL or Ox-VLDL and total RNA from endothelial cells under basal conditions were hybridised to identical microarrays containing 8411 genes. Seven clusters of expression profiles were identified. This pattern was validated by quantitative real-time PCR of selected genes. The intracellular pathway involved in VLDL or Ox-VLDL mediated endothelial responses were also investigated. Results and conclusion: VLDL predominantly activated the ERK1/2 pathway while P38 MAPK was the main target of Ox-VLDL. CREB and NF-KB were activated by both VLDL and Ox-VLDL. Real-time PCR demonstrated that VLDL induced matrix metalloproteinase-2 (5.47±1.74 fold), CD38 (2.38±0.23) and transforming growth factor-
(2.51±0.30) expression. Ox-VLDL was found to induce interleukin-15 (2.10±0.48) and macrophage migration inhibitory factor (3.19±0.07) expression. In addition, several genes implicated in endothelial cell activation and damage/proliferation were identified by the array analysis. Ox-VLDL was found to promote the generation of reactive oxygen species and exert a cytotoxic effect, while VLDL lacks these effects. These findings confirm the involvement of VLDL and Ox-VLDL in endothelial dysfunction and suggest new genes and molecular mechanisms involved in these actions.
KEYWORDS Endothelial cells; Gene expression; VLDL; Lipoprotein; Oxidised
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