Constitutive Expression and Involvement of Cyclooxygenase-2 in Human Megakaryocytopoiesis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 24; no. 3; pp. 607 - 612
• Main Authors: Tanaka, Nobuhito, Sato, Takahiro, Fujita, Hiroshi, Morita, Ikuo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.03.2004; Hagerstown, MD Lippincott
• Subjects: Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Differentiation; Cells, Cultured - cytology; Cells, Cultured - drug effects; Cells, Cultured - enzymology; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Induction; Fetal Blood - cytology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - enzymology; Humans; Infant, Newborn; Isoenzymes - biosynthesis; Isoenzymes - blood; Isoenzymes - genetics; Isoenzymes - physiology; Isoxazoles - pharmacology; Medical sciences; Megakaryocytes - enzymology; Membrane Proteins; Nitrobenzenes - pharmacology; Platelet Count; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - enzymology; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - blood; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - physiology; RNA, Messenger - biosynthesis; Stem Cell Factor - pharmacology; Sulfonamides - pharmacology; Thrombopoiesis - physiology; Thrombopoietin - pharmacology; Thromboxane A2 - biosynthesis; Thromboxane A2 - physiology; Human; Enzyme; Arachidonic acid derivatives; Cyclooxygenase 2; Thromboxane A2; Cyclooxygenase 1; cyclooxygenase-2; cyclooxygenase-1; Cardiovascular disease; platelets; Vascular disease; Platelet; Eicosanoid; Atherosclerosis; Oxidoreductases; megakaryocytopoiesis
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000117181.68309.10

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 CD34cells 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 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.