Role of thromboxane A2 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 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.
Lubrano
Valter
V
C.N.R. Institute of Clinical Physiology, Pisa, Italy.
Baldi
Simona
S
Ferrannini
Ele
E
L'Abbate
Antonio
A
Natali
Andrea
A
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D019332:Endothelin-1 / Q000096:biosynthesis*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism*
D019332:Endothelin-1; C508600:IL6 protein, human; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III