Loss of erythrocyte arginase-1 impairs vasorelaxation due to endothelial GSNOR overexpression and denitrosylation of G protein subunits
Introduction - Overexpression of arginase-1 (ARG1) in red blood cells (RBCs) is associated with endothelial dysfunction, and short-term ARG1 inhibition or l-arginine supplementation restored endothelial function. However, the long-term consequences of ARG1 loss in RBCs and its effects on endothelial...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
July 2026
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| In: |
Redox Biology
Year: 2026, Volume: 94, Pages: 1-11 |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2026.104201 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.redox.2026.104201 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2213231726001990 
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| Author Notes: | Rajinikanth Gogiraju, Beichen Sun, Magdalena L. Bochenek, Ilka Wittig, Flávia Rezende, Melina Lopez, Angela Wirth, Wenjia Zhao, Elsa W. Böhm, Payal Guliani, Kateryna Moiko, Michael Molitor, Philip Wenzel, Marc Freichel, Philipp Lurz, Ralf P. Brandes, Katrin Schäfer |
| Summary: | Introduction - Overexpression of arginase-1 (ARG1) in red blood cells (RBCs) is associated with endothelial dysfunction, and short-term ARG1 inhibition or l-arginine supplementation restored endothelial function. However, the long-term consequences of ARG1 loss in RBCs and its effects on endothelial cells (ECs) are largely unknown. Here, we determined how deletion of ARG1 in RBCs affects blood pressure and vasorelaxation and the role of endothelial NO signaling via the soluble guanylyl cyclase and the S nitrosylation pathway for vascular homeostasis. - Methods - Vascular function was monitored and vasorelaxation studied in C57BL/6 wild-type (WT) and apolipoprotein E deficient (apoE−/−) mice lacking ARG1 in cells of the erythrocyte lineage (RBC.ARG1-knockout, KO) and in mice with inducible deletion of ARG1 in ECs (END.ARG1-KO). Primary cells were analyzed using redox proteomics, immunolabeling and fluorescence microscopy. - Results - Loss of ARG1 in RBCs resulted in significantly elevated plasma nitrite and lower mean and diastolic blood pressure levels, and increased phosphorylation of Vasodilator-Stimulated Phosphoprotein in smooth muscle cells indicated overactivated cyclic GMP signaling. In ECs, nitrosoglutathione reductase (GSNOR) overexpression and denitrosylation of endothelial Guanine Nucleotide Binding Proteins was observed, which may have uncoupled NO signaling from cGMP-mediated vasorelaxation in response to acetylcholine. Importantly, inhibition of GSNOR restored the impaired endothelium-dependent vasorelaxation in RBC.ARG1-KO aortas to levels comparable to RBC.ARG1-WT controls. - Conclusions - Our data support the contribution of RBC-derived NO to blood pressure regulation, but also show that chronically elevated circulating NO levels induce counterregulatory mechanisms in ECs, including increased GSNOR expression and protein S-denitrosylation leading to impaired vasorelaxation despite overactivated cGMP signaling. |
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| Item Description: | Online verfügbar 4 May 2026, Version des Artikels 4 May 2026 Gesehen am 06.07.2026 |
| Physical Description: | Online Resource |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2026.104201 |