Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.
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.
Kobayashi
Takuya
T
Department of Pharmacology, Kyoto University Faculty of Medicine, Japan.
Tahara
Yoshio
Y
Matsumoto
Mayumi
M
Iguchi
Masako
M
Sano
Hideto
H
Murayama
Toshinori
T
Arai
Hidenori
H
Oida
Hiroji
H
Yurugi-Kobayashi
Takami
T
Yamashita
Jun K
JK
Katagiri
Hiroyuki
H
Majima
Masataka
M
Yokode
Masayuki
M
Kita
Toru
T
Narumiya
Shuh
S
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D011464:Epoprostenol / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D044006:Receptors, Epoprostenol / Q000172:deficiency / Q000235:genetics; D017482:Receptors, Thromboxane / Q000172:deficiency / Q000235:genetics; D013928:Thromboxane A2 / Q000378:metabolism*
D001057:Apolipoproteins E; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D044006:Receptors, Epoprostenol; D017482:Receptors, Thromboxane; D018799:Intercellular Adhesion Molecule-1; D013928:Thromboxane A2; D011464:Epoprostenol