© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells
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, United States
* Corresponding author. Tel.: +1 501 296 1401; fax: +1 501 686 6180. Email address: MehtaJL{at}uams.edu
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.
Methods and 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).
Conclusion: 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.
KEYWORDS Aspirin; Endothelial cells; Lectin-like ox-LDL receptor (LOX-1); MAP kinase; Metalloproteinases; Oxidation
Time for primary review 11 days
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