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- Title
Roles of thromboxane A<sub>2</sub> and prostacyclin in the development of atherosclerosis in apoE-deficient mice.
- Authors
Kobayashi, Takuya; Tahara, Yoshio; Matsumoto, Mayumi; Iguchi, Masako; Sano, Hideto; Murayama, Toshinori; Arai, Hidenori; Oida, Hiroji; Yurugi-kobayashi, Takami; Yamashita, Jun K.; Katagiri, Hiroyuki; Majima, Masataka; Yokode, Masayuki; Kita, Toru; Narumiya, Shuh
- Abstract
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-/- 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.
- Subjects
ATHEROSCLEROSIS; THROMBOXANES; PROSTACYCLIN; LABORATORY mice; BLOOD platelets; LEUCOCYTES
- Publication
Journal of Clinical Investigation, 2004, Vol 114, Issue 6, p784
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI200421446