TY - JOUR T1 - A non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease JF - bioRxiv DO - 10.1101/383208 SP - 383208 AU - Vu Thao-Vi Dao AU - Mahmoud H. Elbatreek AU - Martin Deile AU - Pavel I. Nedvetsky AU - Andreas Güldner AU - César Ibarra-Alvarado AU - Axel Gödecke AU - Harald H.H.W. Schmidt Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/25/383208.abstract N2 - Signaling from endothelial nitric oxide (NO) to the heme protein, soluble guanylyl cyclase (sGC), forms vasoprotective cyclic GMP (cGMP). In different disease states such as pulmonary hypertension, this pathway is targeted therapeutically but the underlying pathomechanism leading to its dysfunction is incompletely understood. Here we show in pulmonary artery endothelial cells that this dysfunction is due at least in part to tonic autoinhibition involving NO but not cGMP signaling. Both endogenous NO or pharmacological NO donor compounds that acutely stimulate sGC, chronically decreased both sGC protein and activity. This apparent endogenous feedback was surprisingly independent of canonical cGMP signaling and cGMP-dependent protein kinase. Thiol-sensitive mechanisms known to be relevant in sGC maturation were also not involved. Rather, in vitro and in vivo and in health and disease, tonic NO exposure led to inactivation and degradation of sGC but not of the heme-free apo-sGC isoform, which in some cases increased. Thus, our data establish a bimodal mechanism by which NO regulates sGC, acutely stimulating, chronically inhibiting as part of self-limiting chemical feedback. Of therapeutic importance in disease, our findings caution thus against chronic use of NO donor drugs and suggest that apo-sGC induced by pathological high NO can be recovered in a mechanism-based manner by using apo-sGC activator drugs to re-establish cGMP formation and signaling.One-sentence summary Nitric oxide ubiquitously signals via cyclic GMP, but its feedback regulation is cGMP-independent following a non-canonical redox mechanism that is aggravated under disease conditions. ER -