Key result
Oxidized LDL and F2IP stimulate NO, IL-6, and ET-1 production, with NO driven by TxA2 receptors.
Why the study?
The extent to which the thromboxane A2 (TP) receptor mediates the effects of oxidized LDL on nitric oxide, IL-6, and endothelin-1 release by microvascular endothelial cells was unclear.
In microvascular endothelial cells, oxidized LDL stimulates NO and IL-6 production, but only NO release is largely mediated by the thromboxane A2 receptor.
These in vitro findings extend mechanistic insight into endothelial mediator release; leaves open relevance to clinical microvascular disease.
OBJECTIVE: The aim of this study was to determine to what extent thromboxane A2 (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 (NO2/NO3), ET-1, and IL-6 production were measured following human microvascular endothelial cell 1 exposure to isoprostane-8-epi-PGF2alpha (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: F2IP and both native and oxidized LDL enhanced NO2/NO3. F2IP 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, F2IP had no effect. F2IP 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.
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Lubrano et al. (2008) studied this question. isoprostane-8-epi-PGF2alpha (F2IP) or oxidized LDL with or without TP-receptor blocker SQ29.548 vs. vehicle was evaluated on nitric oxide (NO), interleukin (IL)- 6, and endothelin-1 (ET-1) release. In microvascular endothelial cells, oxidized LDL and F2IP stimulated NO, IL-6, and ET-1 production, with NO release being largely mediated by the thromboxane A2 receptor.
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