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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:607.)
© 2004 American Heart Association, Inc.

Thrombosis

Constitutive Expression and Involvement of Cyclooxygenase-2 in Human Megakaryocytopoiesis

Nobuhito Tanaka; Takahiro Sato; Hiroshi Fujita; Ikuo Morita

From the Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.

Correspondence to Dr I. Morita, Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549 Japan. E-mail morita.cell{at}tmd.ac.jp

Objective— Cyclooxygenase-1 (COX-1), but not COX-2, is expressed in human platelets, and thromboxane A₂ (TXA₂) produced via COX-1 induces platelet aggregation. The objectives of this study were to investigate the expression of COX-1 and COX-2 during platelet differentiation and to determine whether these enzymes are involved in the differentiation.

Methods and Results— CD34⁺ progenitor cells isolated from human cord blood were cultured with thrombopoietin and c-kit ligand. The cells differentiated into megakaryocytes (CD34^-/CD41⁺) after 8 days of culture and into platelets (CD41⁺/prodium iodide^-) after 14 days of culture. The CD34⁺cells expressed a trace of COX-1 gene and no COX-2 gene. On day 5, COX-2 gene expression was observed and continued throughout the remainder of the culture. COX-1 gene expression increased after 8 days of culture. The treatment of this liquid culture with indomethacin, a dual inhibitor of COX-1 and COX-2, and NS-398, a COX-2–specific inhibitor, suppressed megakaryocyte differentiation. In contrast, at a dose of 10^-7 M, mofezolac, which is a highly selective inhibitor of COX-1, did not affect differentiation. NS-398–induced suppression of megakaryocyte differentiation was partly abrogated by stable analogues of TXA₂.

Conclusions— We report here that COX-2 and COX-1 are constitutively expressed in megakaryocytes, and TXA₂ produced by COX-2 plays an important role in megakaryocytopoiesis.

Key Words: megakaryocytopoiesis • cyclooxygenase-1 • cyclooxygenase-2 • platelets • thromboxane A₂

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