Biology subjects

Tupta, B.

Publications and source records attributed to Tupta, B..

2 recordsLinked to original sources

bioRxiv2026

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

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 sGC{beta}1, 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-sGC{beta}1 interaction, suggesting G6PD to be involved in the heme-maturation of sGC{beta}1. 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.

cell biology↗

bioRxiv2025

Myoglobin leaching into the serum of IDA mice is driven by the high activation of sGC under anemic conditions which induces myoglobin expression

Our study reveals that status of the sGC heterodimer or its subsequent activation aligns with active erythropoiesis, and this heterodimer also correlates with the expression of myoglobin (Mb) or HO1. In this study we found that Mb expression which is driven by iron restriction and high sGC activation in iron deficiency anemia (IDA) leaches out more into the serum relative to non-anemic WTs. Tissues from IDA mice of both models developed either by nutritional iron deprivation or by ablation of ferroportin (Fpn) gene or from iron refractory iron deficiency anemia (IRIDA) mice found that Mb expression follows a variable pattern in different tissues but always correlates to the status of the sGC heterodimer or its subsequent activation. Here higher Mb expression happening in anemic (IDA, Fe<5 ppm or IDA, Fpn) or non-anemic WT mice is both due to iron restriction and an elevated sGC heterodimer that corroborated with greater sGC activation. More importantly we find significant leaching of Mb into the serum of these anemic (IDA) mice from both models and our spectral data suggests that this Mb is heme-free. This Mb leaching in anemia is a cumulative impact of Mb secreting out from various tissues including lungs, spleen, skeletal or cardiac muscles where Mb is expressed and not just in the skeletal muscles where Mb expression is low. Based on these findings we construct a working model of anemia, where high activation of sGC under anemic conditions (Fpn ablation or restricted Fe diet) induces Apo-Mb or heme-free Mb expression which can then leach out into the serum. Our findings of Mb leaching are novel and can find further application as a diagnostic strategy in anemia.

biochemistry↗