title: Activation of a retinoic acid receptor pathway by thiazolidinediones induces production of vascular endothelial growth factor/vascular permeability factor in OP9 adipocytes.
abstract: Thiazolidinediones, ligands of peroxisome proliferator-activated receptorγ (PPARγ), are used in the management of type 2 diabetes mellitus. However, they can cause edema, which often leads to a discontinuation of treatment. The mechanism by which thiazolidinediones induce edema is poorly understood. We have confirmed that troglitazone (TGZ), a thiazolidinedione, induced the differentiation of a preadipocyte cell line, OP9, into adipocytes. The differentiated OP9 cells produced vascular permeability factors and the activity was completely neutralized by an antibody against vascular endothelial growth factor (VEGF). TGZ induced the expression of VEGF but not interleukin-6 and monocyte chemoattractant protein-1. 2-chloro-5-nitrobenzanilide (GW9662) blocked both the differentiation and the production of VEGF induced by TGZ. 15-deoxy-Δ(12,14)-Prostaglandin J2, a natural ligand of PPARγ, and another PPARγ agonist, ginkgolic acid, also induced an increase in the expression of VEGE as well as the differentiation of OP9 cells. Indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) with PPARγ activity, up-regulated VEGF expression, but acetylsalicylic acid, a NSAID without PPARγ activity, did not. Although VEGF expression was enhanced under hypoxic conditions, the expression of hypoxia inducible factor and Ets-1 was down-regulated during the TGZ-induced differentiation. On the other hand, retinoic acid enhanced the expression of VEGF despite inhibiting the TGZ-induced differentiation. Moreover, retinoic acid receptor (RAR) β expression was increased by TGZ and retinoic acid. These findings suggested that the major adipocyte-derived vascular permeability factor produced in response to TGZ was VEGF, and a RAR pathway was involved in the production.
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Diseases, Tohoku University, 6-3 Aoba Aramaki, Sendai, Miyagi 980-8578, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kotake
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Hirasawa
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000009:adverse effects / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D045162:Thiazolidinediones / Q000009:adverse effects / Q000494:pharmacology*; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D018168:Receptors, Retinoic Acid; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D000077288:Troglitazone; D001241:Aspirin; D007213:Indomethacin