on April 7, 2005
Published online before print April 7, 2005, doi: 10.1161/01.ATV.0000164805.73558.80
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Submitted on September 13, 2004
Accepted on March 18, 2005
High-Density Lipoproteins Prevent the Oxidized Low-Density Lipoprotein-Induced Endothelial Growth Factor Receptor Activation and Subsequent Matrix Metalloproteinase-2 Upregulation
Fanny Robbesyn ;
From INSERM U-466 and Biochimie IFR-31 (F.R., N.A., C.V., A.-V.C., A.N.-S., R.S.), Faculty of Medicine, University Paul Sabatier, Toulouse, France; INSERM U-563 (R.B.), Centre de Physiopathologie de Toulouse-Purpan, Department Lipoproteines et Mediateurs Lipidiques, IFR-30, Toulouse, France.
* To whom correspondence should be addressed. E-mail: salvayre{at}toulouse.inserm.fr.
Objectives--The atherogenic oxidized low-density lipoprotein (oxLDL) induces the formation of carbonyl-protein adducts and activates the endothelial growth factor receptor (EGFR) signaling pathway, which is now regarded as a central element for signal transduction. We aimed to investigate whether and by which mechanism the anti-atherogenic high-density lipoprotein (HDL) prevents these effects of oxLDL.
Methods and Results--In vascular cultured cells, HDL and apolipoprotein A-I inhibit oxLDL-induced EGFR activation and subsequent signaling by acting through 2 separate mechanisms. First, HDL, like the aldehyde scavenger dinitrophenyl hydrazine, prevented the formation of oxLDL-induced carbonyl-protein adducts and HNE-EGFR adducts. Secondly, HDL enhanced the cellular antioxidant defenses by preventing (through a SR-BI-dependent mechanism) the increase of intracellular reactive oxygen species (ROS) and subsequent EGFR activation triggered by oxLDL or H2O2. A pharmacological approach suggests that this protective effect of HDL is independent of cellular glutathione level and glutathione peroxidase activity, but it requires catalase activity. Finally, we report that oxLDL upregulates both MT1-matrix metalloproteinase-1 (MMP-1) and MMP-2 through an EGFR-dependent mechanism and that HDL inhibits these events.
Conclusions--HDLs block in vitro oxLDL-induced EGFR signaling and subsequent MMP-2 activation by inhibiting carbonyl adducts formation and cellular oxidative stress. These effects of HDL may participate to reduce cell activation, excessive remodeling, and alteration of the vascular wall.
Key words: atherosclerosis • endothelial growth factors • lipoproteins
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