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EMBRYONIC STEM CELLS

High-Glucose-Induced Prostaglandin E₂ and Peroxisome Proliferator-Activated Receptor Promote Mouse Embryonic Stem Cell Proliferation

Department of Veterinary Physiology, Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea

Key Words. High glucose • Embryonic stem cells • Peroxisome proliferator-activated receptor • Prostaglandin E₂

Correspondence: Ho Jae Han, D.V.M., Ph.D., Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea. Telephone: 82-62-530-2831; Fax: 82-62-530-2809; e-mail: hjhan{at}chonnam.ac.kr

Received September 20, 2007; accepted for publication December 14, 2007.
First published online in STEM CELLS EXPRESS   December 20, 2007.



Peroxisome proliferator-activated receptor is a nuclear receptor that has been implicated in blastocyst implantation, cell cycle, and pathogenesis of diabetes. However, the signal cascades underlying this effect are largely unknown in embryo stem cells. This study examined whether or not there is an association between the reactive oxygen species-mediated prostaglandin E₂ (PGE₂)/peroxisome proliferator-activated receptor (PPAR) and the growth response to high glucose levels in mouse ESCs. A high concentration of glucose (25 mM) significantly increased the level of [³H]thymidine incorporation, the level of 5-bromo-2'-deoxyuridine incorporation, and the number of cells. Moreover, 25 mM glucose increased the intracellular reactive oxygen species, phosphorylation of the cytosolic phospholipase A₂ (cPLA₂), and the release of [³H]arachidonic acid ([³H]AA). In addition, 25 mM glucose also increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of PGE₂. Subsequently, high glucose-induced PGE₂ stimulated PPAR expression directly or through Akt phosphorylation indirectly through the E type prostaglandin receptor receptors. The PPAR antagonist inhibited the 25 mM glucose-induced DNA synthesis. Moreover, transfection with a pool of PPAR-specific small interfering RNA inhibited the 25 mM glucose-induced DNA synthesis and G1/S phase progression. Twenty-five millimolar glucose also increased the level of the cell cycle regulatory proteins (cyclin E/cyclin-dependent kinase [CDK] 2 and cyclin D1/CDK 4) and decreased p21^WAF1/Cip1 and p27^Kip1, which were blocked by the inhibition of the cPLA₂, COX-2, or PPAR pathways. In conclusion, high glucose promotes mouse ESC growth in part through the cPLA₂-mediated PGE₂ synthesis and in part through PPAR pathways.

Disclosure of potential conflicts of interest is found at the end of this article.