Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice

Takuya Kobayashi, Yoshio Tahara, Mayumi Matsumoto, Masako Iguchi, Hideto Sano, Toshinori Murayama, Hidenori Arai, Hiroji Oida, Takami Yurugi-Kobayashi, Jun K. Yamashita, Hiroyuki Katagiri, Masataka Majima, Masayuki Yokode, Toru Kita, Shuh Narumiya

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Abstract

Production of thromboxane (TX) A2 and PGI2/ 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.

Original languageEnglish
Pages (from-to)784-794
Number of pages11
JournalJournal of Clinical Investigation
Volume114
Issue number6
DOIs
Publication statusPublished - 2004 Sep
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kobayashi, T., Tahara, Y., Matsumoto, M., Iguchi, M., Sano, H., Murayama, T., Arai, H., Oida, H., Yurugi-Kobayashi, T., Yamashita, J. K., Katagiri, H., Majima, M., Yokode, M., Kita, T., & Narumiya, S. (2004). Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice. Journal of Clinical Investigation, 114(6), 784-794. https://doi.org/10.1172/JCI200421446