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Circ Res. 2017 Jul 7;121(2):137-148. doi: 10.1161/CIRCRESAHA.117.310705. Epub 2017 Jun 5.

Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling.

Author information

1
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 Internal Medicine, Division of Cardiology, University of Texas Houston Medical School (E.M.).
2
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 Internal Medicine, Division of Cardiology, University of Texas Houston Medical School (E.M.). astraub@pitt.edu.

Abstract

RATIONALE:

Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe3+), 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.

KEYWORDS:

guanosine; heme; iron; nitric oxide; reactive oxygen species

PMID:
28584062
PMCID:
PMC5527687
DOI:
10.1161/CIRCRESAHA.117.310705
[Indexed for MEDLINE]
Free PMC Article

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