O13	Induction of prolyl hydroxylase 2 by nitric oxide interferes with the hypoxia induced feedback loop of HIF-1α regulation.
U.Berchner-Pfannschmidt, H.Jamac, B.Trinidad, Chr.Wotzlaw, J.Fandrey
Institut für Physiologie, Universität Duisburg-Essen, Essen, DE.

The transcription factor complex hypoxia-inducible factor 1 (HIF-1) plays a crucial role in cellular adaptation to low oxygen availability. HIF prolyl hydroxylases (PHDs) act as oxygen sensors through posttranslational modification of the HIF-1α subunit, which is sent to proteasomal degradation under normoxia. Reduced activity of PHDs under hypoxia allows HIF-1α to accumulate. In turn, HIF-1α dependent induction of PHD2 establishes a negative feedback loop which might limit HIF-1α accumualtion under hypoxia. Herein we show, that nitric oxide (NO) inhibited PHD activity and induced HIF-1α accumulation under normoxia and hypoxia as long as NO was released into the cell culture system. Thereafter, NO treated cells displayed lowered levels of HIF-1α compared to hypoxic controls due to the HIF-1 dependent increase in PHD2 mRNA and protein levels. Whereas in control cells PHD2 was predominantly localized in the cytoplasm NO induced PHD2 protein was primarily increased in the nucleus. In consequence, NO induced PHD2 levels lead to delayed HIF-1α accumulation in hypoxia and accelerated degradation upon re-oxygenation. We conclude that NO- dependent induction of PHD2 can modulate O2-sensing and interferes with the hypoxia induced feedback loop of HIF-1α regulation.

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