Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling
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Rationale: Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe 3+), is desensitized to NO and limits cGMP production needed for downstream activation of protein kinase G–dependent signaling and blood vessel dilation. Objective: Although reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO-sensitive, reduced state remain poorly understood. Methods and Results: Oxidant challenge studies show that vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein–protein complexes between cytochrome b5 reductase 3, also known as methemoglobin reductase, and oxidized sGC. Genetic knockdown and pharmacological inhibition in vascular smooth muscle cells reveal that cytochrome b5 reductase 3 expression and activity is critical for NO-stimulated cGMP production and vasodilation. Mechanistically, we show that cytochrome b5 reductase 3 directly reduces oxidized sGC required for NO sensitization as assessed by biochemical, cellular, and ex vivo assays. Conclusions: Together, these findings identify new insights into NO–sGC–cGMP signaling and reveal cytochrome b5 reductase 3 as the first identified physiological sGC heme iron reductase in vascular smooth muscle cells, serving as a critical regulator of cGMP production and protein kinase G–dependent signaling.
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Peroxynitrite-mediated oxidation of ETC components such as complex I and complex V results in inhibition of mitochondrial function.
“For example, peroxynitrite-mediated oxidation of ETC components such as complex I and complex V results in inhibition of mitochondrial function (767).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [767]
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BindingDB Entry 50012676: Soluble Guanylate Cyclase Inhibitors Discovered among Natural Compounds.
BindingDB (2022) · UC San Diego · doi:10.7270/q2wd448k
- Authors
- Rahaman, M. M., Nguyen, A. T., Miller, M. P., Hahn, S. A., Sparacino-Watkins, C., Jobbagy, S., Carew, N. T., Cantu-Medellin, N., Wood, K. C., Baty, C. J., Schopfer, F. J., Kelley, E. E., Gladwin, M. T., Martin, E., & Straub, A. C.
- Affiliations
- West Virginia University (US)
- From the Heart, Lung, Blood and Vascular Medicine Institute (M.M.R., A.T.N., M.P.M., S.A.H., C.S.-W., N.T.C., N.C.-M., K.C.W., M.T.G., A.C.S.), Division of Pulmonary, Allergy and Critical Care Medicine (C.S.-W., M.T.G.), Department of Pharmacology and Chemical Biology (S.J., C.J.B., F.J.S., A.C.S.), and Division of Renal-Electrolyte (C.J.B.), University of Pittsburgh, PA; Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown (E.E.K.); and Department of...
- ORCID
- Venue
- Circulation Research
- Published
- 2017-07-07
- Volume
- 121
- Issue
- 2
- Pages
- 137-148
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC5527687
- OpenAlex
- W2623267848
- Cited by
- 92
- References
- 58
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 12 · 2022: 17 · 2021: 14 · 2020: 4 · 2019: 6 · 2018: 11 · 2017: 7
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (15GRNT25700101, R01 HL133864, R01 HL128304, 16GRNT27250146)
- National Institutes of Health (R00 HL‐11290402)
- National Heart, Lung, and Blood Institute (R01HL133864, R01HL128304)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK061296, F30DK108391)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- methemoglobin reductase, soluble guanylate cyclase, cGMP signaling, nitric oxide signaling, vascular smooth muscle cells, protein-protein complex formation, reactive oxygen species, protein kinase G
- MeSH terms
- Soluble Guanylyl Cyclase, Animals, Aorta, Benzoates, Cells, Cultured, Dose-Response Relationship, Drug, Cyclic GMP, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Oxidation-Reduction, Vasodilation, Signal Transduction, Cytochrome-B(5) Reductase, Mice, Rats
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