Role of Thromboxane A2 Receptor on the Effects of Oxidized LDL on Microvascular Endothelium Nitric Oxide, Endothelin-1, and IL-6 Production

• Published in: Microcirculation (New York, N.Y. 1994) N.Y. 1994), 2008-08, Vol.15 (6), p.543-553
• Main Authors: Lubrano, Valter, Baldi, Simona, Ferrannini, Ele, L'abbate, Antonio, Natali, Andrea
• Format: Article
• Language: English
• Subjects: Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelin-1 - biosynthesis; endothelins; endothelium; Humans; Interleukin-6 - biosynthesis; lipoproteins; Lipoproteins, LDL - metabolism; Lipoproteins, LDL - pharmacology; microcirculation; nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type III - metabolism; Oxidation-Reduction; Receptors, Thromboxane A2, Prostaglandin H2 - metabolism
• ISSN: 1073-9688; 1549-8719
• DOI: 10.1080/10739680701884765

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-PGF2α (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.