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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 11, pp 1221–1235 | Cite as

Activation of NQO-1 mediates the augmented contractions of isolated arteries due to biased activity of soluble guanylyl cyclase in their smooth muscle

  • Charlotte M. S. Detremmerie
  • Susan W. S. Leung
  • Paul M. Vanhoutte
ORIGINAL ARTICLE
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Abstract

Earlier studies on isolated arteries demonstrated that the para-quinone thymoquinone, like acute hypoxia, induces augmentation of contractions, depending on biased activity of soluble guanylyl cyclase (sGC), generating inosine-3′,5′-cyclic monophosphate (cyclic IMP) rather than guanosine-3′,5′-cyclic monophosphate (cyclic GMP). NAD(P)H:quinone oxidoreductase 1 (NQO-1), the enzyme responsible for biotransformation of quinones into hydroquinones, was examined for its involvement in these endothelium-dependent augmentations, establishing a link between the metabolism of quinones by NQO-1 and biased sGC activity. Isolated arteries of Sprague-Dawley rats (aortae and mesenteric arteries) and farm pigs (coronary arteries) were studied for measurement of changes in tension and collected to measure NQO-1 activity or its protein level. β-lapachone, an ortho-quinone and hence substrate of NQO-1, increased the activity of the enzyme and augmented contractions in arteries with endothelium. This augmentation was inhibited by endothelium removal and inhibitors of endothelial NO synthase (eNOS), sGC, or NQO-1; in preparations without endothelium or treated with an eNOS inhibitor, it was restored by the NO donor DETA NONOate and by ITP and cyclic IMP, revealing biased sGC activity as the underlying mechanism, as with thymoquinone. Hydroquinone, the end product of quinone metabolism by NQO-1, augmented contractions depending on sGC activation but in an endothelium-independent manner. In coronary arteries, repeated acute hypoxia caused similar augmentations as those to quinones that were inhibited by the NQO-1 inhibitor dicoumarol. Augmentations of contraction observed with different naturally occurring quinones and with acute hypoxia are initiated by quinone metabolism by NQO-1, in turn interfering with the NO/biased sGC pathway, suggesting a possibly detrimental role of this enzyme in ischemic cardiovascular disorders.

Keywords

Vasoconstriction Biased soluble guanylyl cyclase (sGC) activity Cyclic IMP Quinones Hydroquinone Hypoxic augmentation NAD(P)H:quinone oxidoreductase 1 (NQO-1) 

Abbreviations

Cyclic GMP

Guanosine-3′,5′-cyclic monophosphate

Cyclic IMP

Inosine-3′,5′-cyclic monophosphate

DETA NONOate

Diethylenetriamine NONOate

DETCA

Diethyldithiocarbamate

DMSO

Dimethylsulfoxide

eNOS

Endothelial nitric oxide synthase

ES936

5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]-1H-indole-4,7-dione

ITP

Inosine triphosphate

l-NAME

Nω-nitro-l-arginine methyl ester hydrochloride

NQO-1

NAD(P)H:quinone oxidoreductase 1

NO

Nitric oxide

ODQ

1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one

ROS

Reactive oxygen species

SDS

Sodium dodecyl sulfate

sGC

Soluble guanylyl cyclase

TBS

Tris-buffered saline

VAS-2870

1,3-Benzoxazol-2-yl-3-benzyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl sulfide

Notes

Acknowledgements

The authors would like to thank Ms. Yee Har Chung and Mr. Godfrey Man for their excellent technical assistance and Ms. Ivy Wong for her editorial and administrative support.

Author contribution

CD, SL, and PV conceived and designed the research. CD conducted the experiments and analyzed the data. CD, SL, and PV wrote the manuscript. All authors read and approved the final version of the manuscript.

Funding

This work was supported by the Health and Medical Research Fund [15162231] of the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region and by the General Research Fund [17112914] of the Hong Kong Research Grant Council.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

210_2018_1548_MOESM1_ESM.pdf (373 kb)
ESM 1 (PDF 372 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina

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