Nitric oxide impairs normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases

Eric Metzen, Jie Zhou, Wolfgang Jelkmann, Joachim Fandrey, Bernhard Brüne

328 Citations (Scopus)


Hypoxia inducible factor-1 (HIF-1) is the master regulator of metabolic adaptation to hypoxia. It is appreciated that HIF-1α accumulation is achieved under normoxic conditions by e.g., nitric oxide. We determined molecular mechanisms of HIF-1α accumulation under the impact of S-nitrosoglutathione (GSNO). In human embryonic kidney cells GSNO provoked nuclear accumulation of HIF-1α. This appeared unrelated to gene transcription and protein translation, thus pointing to inhibition of HIF-1α degradation. Indeed, GSNO as well as the hypoxia mimic CoCl 2 decreased ubiquitination of HIF-1α and GSNO-induced HIF-1α failed to coimmunoprecipitate with pVHL (von Hippel Lindau protein). Considering that HIF-1α-pVHL interactions require prolyl hydroxylation of HIF-1α, we went on to demonstrate inhibition of HIF-1α prolyl hydroxylases (PHDs) by GSNO. In vitro HIF-1α-pVHL interactions revealed that GSNO dose-dependently inhibits PHD activity but not the interaction of a synthetic peptide resembling the hydroxylated oxygen-dependent degradation domain of HIF-1α with pVHL. We conclude that GSNO-attenuated prolyl hydroxylase activity accounts for HIF-1α accumulation under conditions of NO formation during normoxia and that PHD activity is subject to regulation by NO.

Original languageEnglish
JournalMolecular Biology of the Cell
Issue number8
Pages (from-to)3470-3481
Number of pages12
Publication statusPublished - 01.08.2003

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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