Role of thromboxane A2 receptor on the effects of oxidized LDL on microvascular endothelium nitric oxide, endothelin-1, and IL-6 production

Microcirculation. 2008 Aug;15(6):543-53. doi: 10.1080/10739680701884765.

Abstract

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.

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelin-1 / biosynthesis*
  • Humans
  • Interleukin-6 / biosynthesis*
  • Lipoproteins, LDL / metabolism*
  • Lipoproteins, LDL / pharmacology
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidation-Reduction
  • Receptors, Thromboxane A2, Prostaglandin H2 / metabolism*

Substances

  • Endothelin-1
  • IL6 protein, human
  • Interleukin-6
  • Lipoproteins, LDL
  • Receptors, Thromboxane A2, Prostaglandin H2
  • oxidized low density lipoprotein
  • Nitric Oxide
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III