کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1964372 | 1058545 | 2007 | 8 صفحه PDF | دانلود رایگان |
15-deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2) is a peroxisome-activated proliferator receptor-γ (PPARγ) agonist which contains an α,β-unsaturated electrophilic ketone involved in nucleophilic addition reactions to thiols. Here we studied its effect on hypoxia-inducible factor-1α (HIF-1α) in human proximal tubular cells HK-2. 15d-PGJ2 induced stabilization of HIF-1α protein, without affecting HIF-1α mRNA levels or proteasome activity, leading to its nuclear accumulation and activation of HIF-induced transcription. Accumulation of HIF-1α was unaffected by selective PPARγ blockade nor mimicked by the PPARγ agonists ciglitazone and 9,10-dihydro-15d-PGJ2. N-acetylcysteine, reduced glutathione (GSH) or dithiothreitol (i.e. agents that act as thiol reducing agents and/or increase the GSH content), but not reactive oxygen species (ROS) scavengers, prevented 15d-PGJ2-induced HIF-1α accumulation whereas the inhibitor of GSH synthesis buthionine sulfoximine cooperated with 15d-PGJ2 to accumulate HIF-1α. Finally, HIF-1α expression was increased by the electrophilic α,β-unsaturated compounds acrolein and PGA2, but not by 9,10-dihydro-15d-PGJ2, which lacks the electrophilic cyclopentenone moiety. Taken together, these results point out to a new mechanism to increase pharmacologically the cell levels of HIF-1α through the electrophilic reaction of α,β-unsaturated ketones with thiol groups.
Journal: Cellular Signalling - Volume 19, Issue 10, October 2007, Pages 2098–2105