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Keap1 controls protein S-nitrosation and apoptosis-senescence switch in endothelial cells.

Aleksandra Kopacz | Damian Klóska | Bartosz Proniewski | Dominik Cysewski | Nicolas Personnic | Aleksandra Piechota-Polańczyk | Patrycja Kaczara | Agnieszka Zakrzewska | Henry Jay Forman | Józef Dulak | Alicja Józkowicz | Anna Grochot-Przęczek
Redox biology | 2020

Premature senescence, a death escaping pathway for cells experiencing stress, is conducive to aging and cardiovascular diseases. The molecular switch between senescent and apoptotic fate remains, however, poorly recognized. Nrf2 is an important transcription factor orchestrating adaptive response to cellular stress. Here, we show that both human primary endothelial cells (ECs) and murine aortas lacking Nrf2 signaling are senescent but unexpectedly do not encounter damaging oxidative stress. Instead, they exhibit markedly increased S-nitrosation of proteins. A functional role of S-nitrosation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage and redirection of ECs to premature senescence. S-nitrosation and senescence are mediated by Keap1, a direct binding partner of Nrf2, which colocalizes and precipitates with nitric oxide synthase (NOS) and transnitrosating protein GAPDH in ECs devoid of Nrf2. We conclude that the overabundance of this "unrestrained" Keap1 determines the fate of ECs by regulation of S-nitrosation and propose that Keap1/GAPDH/NOS complex may serve as an enzymatic machinery for S-nitrosation in mammalian cells.

Pubmed ID: 31491600

Associated grants

  • Agency: NIEHS NIH HHS, United States
    Id: R01 ES023864
  • Agency: NIEHS NIH HHS, United States
    Id: R56 ES023864

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