Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

Vu Thao-Vi Dao, Mahmoud H. Elbatreek, Martin Deile, Pavel Nedvetsky, Andreas Gueldner, Cesar Ibarra-Alvarado, Axel Goedecke, Harald H. H. W. Schmidt

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Abstract

Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This effect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation
Original languageEnglish
Article number10012
Number of pages10
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 19 Jun 2020

Keywords

  • SOLUBLE GUANYLATE-CYCLASE
  • SHOCK-PROTEIN 90
  • ENDOTHELIAL-CELLS
  • INDEPENDENT ACTIVATION
  • OXIDATIVE STRESS
  • HEME OXYGENASE-1
  • VASCULAR SYSTEM
  • SEPTIC SHOCK
  • KINASE-I
  • EXPRESSION

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