Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice

J Clin Invest. 2004 Sep;114(6):784-94. doi: 10.1172/JCI21446.


Production of thromboxane (TX) A2 and PG I2/prostacyclin (PGI2) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE-/-TP-/- mice exhibited a significant delay in atherogenesis, and apoE-/-IP-/- mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE-/-IP-/- mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE-/-TP-/- mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE-/-IP-/- and apoE-/-TP-/- mice, respectively, than in those of apoE-/- mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE-/-IP-/- mice than in either apoE-/-TP-/- or apoE-/- mice. We conclude that TXA2 promotes and PGI2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Arteriosclerosis / blood
  • Arteriosclerosis / immunology
  • Arteriosclerosis / pathology*
  • Arteriosclerosis / physiopathology
  • Epoprostenol / metabolism*
  • Intercellular Adhesion Molecule-1 / genetics
  • Macrophages / cytology
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Platelet Aggregation
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Receptors, Epoprostenol / deficiency
  • Receptors, Epoprostenol / genetics
  • Receptors, Thromboxane / deficiency
  • Receptors, Thromboxane / genetics
  • Thromboxane A2 / metabolism*


  • Apolipoproteins E
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptors, Epoprostenol
  • Receptors, Thromboxane
  • Intercellular Adhesion Molecule-1
  • Thromboxane A2
  • Epoprostenol