Published online before print April 7, 2005, doi: 10.1161/01.ATV.0000164805.73558.80
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
High-Density Lipoproteins Prevent the Oxidized Low-Density Lipoprotein–Induced Endothelial Growth Factor Receptor Activation and Subsequent Matrix Metalloproteinase-2 Upregulation
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.
Correspondence to R. Salvayre or A. Negre-Salvayre, Biochimie, INSERM U466, IFR-31, CHU Rangueil, 1, avenue Jean Poulhès, TSA-50032, 31059 Toulouse Cedex 9, France. E-mail salvayre{at}toulouse.inserm.fr or anesalv@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 4-hydroxynonenal (HNE)–EGFR adducts. Secondly, HDL enhanced the cellular antioxidant defenses by preventing (through a scavenger receptor class B-1 (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 membrane type 1 (MT1)-matrix metalloproteinase-1 (MT1-MMP) 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.
Oxidized LDLs induce EGFR activation and subsequent MMP-2 activation. HDLs inhibit these events by 2 separate mechanisms, ie, by blocking carbonyl–protein adduct formation and by inhibiting the oxLDL-induced and H2O2-induced intracellular ROS increase, through a catalase-dependent process. This may contribute to reduce cell activation, excessive remodeling, and vascular wall alteration.
Key Words: atherosclerosis • endothelial growth factors • lipoproteins
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