High-density lipoproteins prevent the oxidized low-density lipoprotein-induced epidermal [corrected] growth factor receptor activation and subsequent matrix metalloproteinase-2 upregulation.
OBJECTIVE
The atherogenic oxidized low-density lipoprotein (oxLDL) induces the formation of carbonyl-protein adducts and activates the epidermal [corrected] 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.


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.
Robbesyn
Fanny
F
INSERM U-466 and Biochimie IFR-31, Faculty of Medicine, University Paul Sabatier, Toulouse, France.
Augé
Nathalie
N
Vindis
Cécile
C
Cantero
Anne-Valérie
AV
Barbaras
Ronald
R
Negre-Salvayre
Anne
A
Salvayre
Robert
R
D000447:Aldehydes / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D004347:Drug Interactions; D066246:ErbB Receptors / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D050050:Protein Carbonylation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000447:Aldehydes; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D061965:Matrix Metalloproteinase Inhibitors; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D006861:Hydrogen Peroxide; D002374:Catalase; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2; C027576:4-hydroxy-2-nonenal