LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells.
BACKGROUND
Oxidized LDL (ox-LDL) accumulation in the atherosclerotic region may enhance plaque instability. Both accumulation of ox-LDL and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. This study was designed to examine the role of LOX-1 in the modulation of metalloproteinases (MMP-1 and MMP-3) in human coronary artery endothelial cells (HCAECs).


RESULTS
HCAECs were incubated with ox-LDL (10 to 80 micro g/mL) for 1 to 24 hours. Ox-LDL increased the expression of MMP-1 (collagenase) and MMP-3 (stromelysin-1) in a concentration- and time-dependent manner. Ox-LDL also increased collagenase activity. Ox-LDL did not significantly affect the expression of tissue inhibitors of metalloproteinases. Native LDL had no effect on the expression of MMPs. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1, because pretreatment of HCAECs with a blocking antibody to LOX-1 (JTX92, 10 micro g/mL) prevented the expression of MMPs in response to ox-LDL (P<0.01). In parallel experiments, ox-LDL caused the activation of protein kinase C (PKC), which was inhibited by LOX-1 antibody. The PKC-beta isoform played a critical role in the expression of MMPs, because the PKC-beta inhibitor hispidin reduced ox-LDL-induced activation of PKC and the expression of MMPs. Other PKC subunits (alpha, gamma, and epsilon) did not affect the expression of MMPs.


CONCLUSIONS
These findings indicate that ox-LDL, via LOX-1 activation, modulates the expression and activity of MMPs in HCAECs. In this process, activation of the PKC-beta subunit plays an important signaling role.
Li
Dayuan
D
Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock 72205, USA.
Liu
Ling
L
Chen
Hongjiang
H
Sawamura
Tatsuya
T
Ranganathan
Subramanian
S
Mehta
Jawahar L
JL
D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D021122:Protein Subunits; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D019715:Tissue Inhibitor of Metalloproteinase-1; C099252:oxidized low density lipoprotein; D019716:Tissue Inhibitor of Metalloproteinase-2; D011493:Protein Kinase C; D017364:Collagenases; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1