Role of thromboxane A(2) receptor on the effects of oxidized LDL on microvascular endothelium nitric oxide, endothelin-1, and IL-6 production

Objective: The aim of this study was to determine to what extent thromboxane A(2) (TP) receptor mediates the effect of oxidated low-density lipoprotein (LDL) on nitric oxide (NO), interleukin (IL)-6, and endothelin-1 (ET-1) release by microvascular endothelial cells. Methods: Endothelial nitric oxide synthase (eNOS), nitrites and nitrates (NO(2)/NO(3)), ET-1, and IL-6 production were measured following human microvascular endothelial cell 1 exposure to isoprostane-8-epi-PGF(2 alpha) (F2IP), a natural agonist of the TP receptor present in oxidized LDL, or native, low-, or medium-oxidized LDL either with the TP-receptor blocker, SQ29.548, or its vehicle. Results: F(2)IP and both native and oxidized LDL enhanced NO(2)/NO(3). F(2)IP through the TP receptor stimulated eNOS (eight-fold), while the oxidized LDL effect (two-to five-fold) was only partially prevented by SQ29.548. While LDL concentration and degree of oxidation synergistically and independent of SQ29.548 stimulated IL-6, F(2)IP had no effect. F(2)IP induced a modest (+50%) increase in ET-1. LDL, independent of concentration or degree of oxidation, stimulated (+120%) ET-1 production, and this effect was only partially attenuated by SQ29.548. Conclusions: In microvascular endothelial cells, LDL concentration and degree of oxidation synergistically stimulate NO and IL-6 production, but only NO release is largely mediated by the TP receptor. LDL facilitates ET-1 release independent of concentration and degree of oxidation; TP-receptor stimulation is only partially responsible for this effect.