on January 15, 2004
Published online before print January 15, 2004, doi: 10.1161/01.ATV.0000117181.68309.10
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Submitted on December 1, 2003
Accepted on December 21, 2003
Constitutive Expression and Involvement of Cyclooxygenase-2 in Human Megakaryocytopoiesis
Nobuhito Tanaka ;
From the Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
* To whom correspondence should be addressed. 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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