15‐deoxy‐Δ12,14 prostaglandin J2‐induced heme oxygenase‐1 in megakaryocytes regulates thrombopoiesis

• Published in: Journal of thrombosis and haemostasis 2009-01, Vol.7 (1), p.182-189
• Main Authors: O'BRIEN, J. J., BAGLOLE, C. J., GARCIA‐BATES, T. M., BLUMBERG, N., FRANCIS, C. W., PHIPPS, R. P.
• Format: Article
• Language: English
• Subjects: heme oxygenase; megakaryocyte; platelet; thrombopoiesis
• ISSN: 1538-7933; 1538-7836
• DOI: 10.1111/j.1538-7836.2008.03191.x

Background: Platelet production is an intricate process that is poorly understood. Recently, we demonstrated that the natural peroxisome proliferator‐activated receptor gamma (PPARγ) ligand, 15‐deoxy‐Δ12,14 prostaglandin J2 (15d‐PGJ2), augments platelet numbers by increasing platelet release from megakaryocytes through the induction of reactive oxygen species (ROS). 15d‐PGJ2 can exert effects independent of PPARγ, such as increasing oxidative stress. Heme oxygenase‐1 (HO‐1) is a potent antioxidant and may influence platelet production. Objectives: To further investigate the influence of 15d‐PGJ2 on megakaryocytes and to understand whether HO‐1 plays a role in platelet production. Methods: Meg‐01 cells (a primary megakaryoblastic cell line) and primary human megakaryocytes derived from cord blood were used to examine the effects of 15d‐PGJ2 on HO‐1 expression in megakaryocytes and their daughter platelets. The role of HO‐1 activity in thrombopoiesis was studied using established in vitro models of platelet production. Results and conclusions: 15d‐PGJ2 potently induced HO‐1 protein expression in Meg‐01 cells and primary human megakaryocytes. The platelets produced from these megakaryocytes also expressed elevated levels of HO‐1. 15d‐PGJ2‐induced HO‐1 was independent of PPARγ, but could be replicated using other electrophilic prostaglandins, suggesting that the electrophilic properties of 15d‐PGJ2 were important for HO‐1 induction. Interestingly, inhibiting HO‐1 activity enhanced ROS generation and augmented 15d‐PGJ2‐induced platelet production, which could be attenuated by antioxidants. These new data reveal that HO‐1 negatively regulates thrombopoiesis by inhibiting ROS.