Abstract 73: Selective Inhibition of COX-1 & 2 Results in Reprogramming of Adipocyte Gene Expression and Adipogenesis in Mesenchymal Stem Cells: Role of 20-HETE-derived 20-OH-PGE2
Eicosanoids are increasingly recognized to play a central role in modulating the process of adipogenesis in human bone marrow derived mesenchymal stem cells (MSCs) where prostaglandin E2 (PGE2) has been shown to negatively regulate adipogenesis. 20-Hydroxyeicosatetraenoic acid (20-HETE), a product of the cytochrome P450 (CYP)-catalyzed ω-hydroxylation of arachidonic acid, induces oxidative stress, and in clinical studies, is associated with increased BMI and metabolic syndrome. In this study we sought to characterize the effects of exogenous 20-HETE on MSC-derived adipogenesis. 20-HETE dose-dependently (0.01-1 μM) increased (p<0.05) adipogenesis (0.11±0.001, 0.12±0.007, 0.14±0.015 and 0.16±0.013) in MSCs, an effect not attenuated by concurrent administration of a putative 20-HETE antagonist (DKB-H1-40-32). However, a selective cyclooxygenase-2 (COX-2) inhibitor prevented (0.071±0.004 vs 0.16±0.013) this pro-adipogenic effect of 20-HETE thus raising the possibility that a metabolic product of 20-HETE is mediating its effects on MSCs. We next exposed these MSCs to exogenous 20-OH-PGE2, an endogenous COX-2 derived product of 20-HETE. Treatment with 20-OH-PGE2 also dose-dependently enhanced (0.08±0.02, 0.14±0.01, 0.21±0.01 and 0.4±0.02) adipogenesis and lipid accumulation in MSC-derived adipocytes. In addition, in cells undergoing COX-1 &2 blockade, treatment of MSCs with PGE2 shifted the dose response curve of 20-OH-PGE2 to the right, indicative of a competitive antagonistic interactions of COX-1 derived PGE2 and COX-2-derived 20-OH-PGE2 on the process of adipogenesis. Both 20-HETE and 20-OH-PGE2-induced adipocyte hypertrophy was accompanied with increased expression of adipogenic regulators, PPARδ, C/EBPα and MEST1. Taken together we show for the first time that 20-HETE-derived COX-2-dependent 20-OH-PGE2 could enhance lipid accumulation and induces adipocyte hypertrophy in MSC undergoing adipogenic differentiation. We also propose that effects of COX-1 derived PGE2, a known inhibitor of adipocyte differentiation, are opposed by endogenous 20-OH-PGE2 production which appears to predominantly COX-2 dependent.
- © 2012 by American Heart Association, Inc.