Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic

Ghosh, Arnab; Sumi, Mamta P.; Tupta, Blair; Okamoto, Toshihiro; Aulak, Kulwant S.; Tsutsui, Masato; Shimokawa, Hiroaki; Erzurum, Serpil C.; Stuehr, Dennis J.

doi:10.1016/j.redox.2022.102478

Cited by 19 publications

(28 citation statements)

References 81 publications

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“…This suggests that NO concentrations of only 100 pM to 5 nM were being reached in our cell cultures yet still could stimulate cells to allocate heme into apo-IDO1 and apo-TDO. Such concentrations of NO can enable metal-nitrosyl formation, for example NO binding to the heme in sGC to activate its cGMP synthesis, and also can drive cells to allocate heme into apo-sGCβ (44,46), but are somewhat lower than the NO concentrations required to stimulate cells to phosphorylate ERK or Akt, and are 20 to 80 times lower than the NO concentrations required to promote HIF-1α stabilization or P53 phosphorylation in cells (47). Thus, stimulating cell heme allocation may be one of the more sensitive NO effects in biology.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine Dioxygenase and Tryptophan Dioxygenase Activities are Regulated through Control of Cell Heme Allocation by Nitric Oxide

Biswas

Stuehr

2022

Preprint

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Indoleamine-2, 3-dioxygenase (IDO1) and Tryptophan-2, 3-dioxygenase (TDO) catalyze the conversion of L-tryptophan to N-formyl- kynurenine and thus play primary roles in metabolism, inflammation, and tumor immune surveillance. Because their activities depend on their heme contents which range from 30- 60% heme-saturated in biological settings and go up or down in a dynamic manner, we studied how their heme levels may be impacted by nitric oxide (NO) in mammalian cells. We utilized cells expressing TDO or IDO1 either naturally or via transfection and determined their activities, heme contents, and expression levels as a function of NO exposure. We found NO has a bimodal effect: A narrow range of very low NO exposure promoted cells to allocate heme into TDO and IDO1 and boosted their activities several fold, while beyond this range the NO exposure transitioned to have a negative impact on their heme contents and activities. NO did not alter dioxygenase protein expression levels and its bimodal impact was observed when NO was released by a chemical donor or was generated naturally by immune-stimulated macrophage cells. NO-driven heme allocations to IDO1 and TDO required participation of a GAPDH- heme complex and for IDO1 required chaperone Hsp90 activity. Thus, cells can up- or down-regulate their IDO1 and TDO activities through a bimodal control of heme allocation by NO. This mechanism has important biomedical implications and helps explain why the IDO1 and TDO activities in animals go up and down in response to immune stimulation.

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Section: Discussionmentioning

confidence: 99%

Indoleamine Dioxygenase and Tryptophan Dioxygenase Activities are Regulated through Control of Cell Heme Allocation by Nitric Oxide

Biswas

Stuehr

2022

Preprint

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“…Western blots, immunoprecipitations (IPs) and immunohistological staining: Western blots, IPs and immunostaining were performed using standard protocols and as previously mentioned [ 24 ] (see details in the SI). Band intensities on westerns were quantified using Image J quantification software (NIH).…”

Section: Methodsmentioning

confidence: 99%

“…Olis Clarity spectroscopy: The analysis of Hb heme in the lung tissue supernatants was done by using the Olis Clarity spectrophotometer [ 24 ], which can record the heme spectra of suspensions or solutions in particulate form. Here the absorption spectra was collected with an integrating sphere detector.…”

Section: Methodsmentioning

confidence: 99%

“…However based on the generated NO concentrations these effects can work both ways to make or break cellular events. For example a recent finds suggests that low doses of NO promote hemeprotein maturation or cause heme-insertion while higher NO doses are inhibitory to the process [ 24 ]. This suggests that a fine balance may exist in cell systems to maintain optimum physiological NO levels under normal healthy conditions [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hemoglobin resident in the lung epithelium is protective for smooth muscle soluble guanylate cyclase function

Sumi¹,

Tupta²,

Roychowdhury³

et al. 2023

Redox Biology

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“…Nitric oxide (NO) was an important immunostimulant engaged in vascular regulation and immune response [ 14 , 15 ]. No induced the expression of endogenous angiogenic factors [ 16 , 17 ], thereby normalizing tumor vasculature to improve blood perfusion, relieving tumor hypoxia, and regulating the transition from an immunosuppressive to an immune-supportive TME [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

et al. 2023

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Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy. Graphical Abstract

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Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic

Cited by 19 publications

References 81 publications

Indoleamine Dioxygenase and Tryptophan Dioxygenase Activities are Regulated through Control of Cell Heme Allocation by Nitric Oxide

Indoleamine Dioxygenase and Tryptophan Dioxygenase Activities are Regulated through Control of Cell Heme Allocation by Nitric Oxide

Hemoglobin resident in the lung epithelium is protective for smooth muscle soluble guanylate cyclase function

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

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