Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells.
BACKGROUND
Aspirin is thought to exert salutary effects in vascular disease states by inhibiting platelet aggregation. Endothelial activation, accumulation of oxidized low-density lipoprotein (ox-LDL) and intense inflammation also characterize atherosclerotic plaque in acute myocardial ischemia. Ox-LDL induces expression of lectin-like receptors (LOX-1) on endothelial cells and leads to the expression of matrix metalloproteinases (MMPs), which destabilize the atherosclerotic plaque. We hypothesized that aspirin may interfere with LOX-1 expression and subsequent MMP activation.


RESULTS
Cultured human coronary artery endothelial cells (HCAECs) were incubated with aspirin (1-5 mM), sodium salicylate (5 mM) or the cyclo-oxygenase inhibitor indomethacin (0.25 mM) before treatment with ox-LDL. Aspirin, in a dose- and time-dependent fashion, reduced ox-LDL-mediated LOX-1 expression (P<0.01). Ox-LDL also increased MMP-1 expression and activity, and treatment of HCAECs with aspirin decreased this effect (P<0.01). Ox-LDL also enhanced the activity of p38MAPK in HCAECs, and aspirin blocked this effect of ox-LDL (P<0.01). Treatment of HCAECs with salicylate, but not indomethacin, resulted in a suppression of LOX-1 expression, an effect similar to that of aspirin. Importantly, both aspirin and salicylate, but not indomethacin, decreased superoxide anion generation in ox-LDL-treated HCAECs (P<0.05).


CONCLUSIONS
These observations suggest that aspirin inhibits ox-LDL-mediated LOX-1 expression and interferes with the effects of ox-LDL in intracellular signaling (p38MAPK activation) and subsequent MMP-1 activity. These novel effects of aspirin may complement its platelet inhibitory effect in acute myocardial ischemia.
Mehta
J L
JL
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, 4301 West Markham St., #532, Little Rock, AR 72205-7199, USA. MehtaJL@uams.edu
Chen
J
J
Yu
F
F
Li
D Y
DY
D000838:Anions / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D002478:Cells, Cultured; D003331:Coronary Vessels; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D012459:Salicylates / Q000494:pharmacology; D051127:Scavenger Receptors, Class E; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000838:Anions; D016861:Cyclooxygenase Inhibitors; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D012459:Salicylates; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D013481:Superoxides; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D001241:Aspirin; D007213:Indomethacin