NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma

Arnab Ghosh; Mamta P. Sumi; Cynthia Koziol-White; Blair Tupta; Ling Wang; Chaitali Ghosh; William F. Jester; Reynold A. Panettieri; Dennis J. Stuehr

doi:10.64898/2026.05.06.723287

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NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma

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NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma

Arnab Ghosh, Mamta P. Sumi, Cynthia Koziol-White, Blair Tupta, Ling Wang, Chaitali Ghosh, William F. Jester, Reynold A. Panettieri and Dennis J. Stuehr

bioRxiv

Cold Spring Harbor Laboratory Preprints

05/11/2026

DOI: 10.64898/2026.05.06.723287

PMCID: PMC13192709

PMID: 42182200

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Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Since NO can modulate mesenchymal cell function, we posit that NO can modulate gene expression associated with excitation-contraction coupling. Our study shows that treating asthma-derived HASMCs with a low dose of NO plus sGC stimulator BAY-41, in most cases sensitized smooth muscle sGC towards activation via an elevated sGC heterodimer and in some cases also improved sGCβ1, catalase, Cyb5r3 or Trx1 expression (n=24 non-asthma and n=25 asthma). Interestingly we found that majority of asthma HASMCs showed a marked downregulation of G6PD expression inducing a low GSH/GSSG ratio in asthma, and these findings were replicated in murine lungs of allergic asthma (OVA and CFA/HDM). Studies with HEK/COS-7 cells showed G6PD synergizing with hsp90 in enabling sGC heme-maturation. G6PD overexpression in HASMCs enhanced the sGC heterodimerization while silencing of endogenous G6PD abrogated it. Complementation of these cellular results with whole animal models of G6PD deficiency or overexpression provided verification to our findings. Mouse lung tissue from the humanized variant of G6PD deficiency, V68M (G6PD A-deficiency) showed significant downregulation in the sGC heterodimer, with a concomitant reduction in its NO heme-dependent activity, thereby showing that G6PD deficiency lowers sGC heme. Conversely, G6PD overexpressing mouse lung tissue displayed an elevated sGC heterodimer and also showed a robust G6PD-sGCβ1 interaction, suggesting G6PD to be involved in the heme-maturation of sGCβ1. While G6PD maintains the cell redox by generating NADPH, its new role in regulating sGC maturation links sGC dysfunction in asthma to G6PD deficiency and may potentially uncover new targets for asthma treatment.

Details

Title: Subtitle: NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma
Creators: Arnab Ghosh - Cleveland Clinic
Mamta P. Sumi - Cleveland Clinic
Cynthia Koziol-White - Rutgers, The State University of New Jersey
Blair Tupta - Cleveland Clinic
Ling Wang - University of Iowa
Chaitali Ghosh - Cleveland Clinic
William F. Jester - Rutgers, The State University of New Jersey
Reynold A. Panettieri - Rutgers, The State University of New Jersey
Dennis J. Stuehr - Cleveland Clinic
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.64898/2026.05.06.723287
PMID: 42182200
PMCID: PMC13192709
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory Preprints
Language: English
Date posted: 05/11/2026
Academic Unit: Orthopedics and Rehabilitation
Record Identifier: 9985164605102771

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