Journal article
NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma
Redox biology, Vol.95, 104262
09/2026
DOI: 10.1016/j.redox.2026.104262
PMID: 42308693
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.
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•Low dose of NO can revive the smooth muscle sGC towards NO activation by elevating the sGC heterodimer•G6PD is involved in the maturation of sGC and elevates the sGC heterodimer•Low levels of G6PD are found in asthma HASMCs with low GSH/GSSG ratio•Low NO can improve expression of sGCβ1, catalase, Cyb5r3 or Trx1
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 ClinicMamta P. Sumi - Cleveland ClinicCynthia Koziol-White - Rutgers, The State University of New JerseyBlair Tupta - Cleveland ClinicLing Wang - University of IowaChaitali Ghosh - Cleveland ClinicWilliam F. Jester - Rutgers, The State University of New JerseyReynold A. Panettieri - Rutgers, The State University of New JerseyDennis J. Stuehr - Cleveland Clinic
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.95, 104262
- DOI
- 10.1016/j.redox.2026.104262
- PMID
- 42308693
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier B.V; AMSTERDAM
- Grant note
- National Institute of Health: R56HL139564, R01HL150049, R01-HL166594, R01NS137230, GM148664
We acknowledge Dr. Kewal Asosingh for providing lung tissue samples from murine asthma models. This work was supported by National Institute of Health Grants R56HL139564 and R01HL150049 (A. G.) , Grants for R.A.P. (R01-HL166594) , C.G. (R01NS137230) and D.J.S. (GM148664) .
- Language
- English
- Electronic publication date
- 06/15/2026
- Date published
- 09/2026
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9985175468102771
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