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Cardiovascular Research Advance Access originally published online on November 26, 2008
Cardiovascular Research 2009 81(4):750-757; doi:10.1093/cvr/cvn326
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Norfuraneol dephosphorylates eNOS at threonine 495 and enhances eNOS activity in human endothelial cells

Christoph A. Schmitt1, Elke H. Heiss1, Yasmin Aristei2, Theodor Severin3 and Verena M. Dirsch1,*

1 Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
2 Department of Chemistry, Laboratory for Chemometrics and Chemoinformatics, University of Perugia, Perugia, Italy
3 Department of Pharmacy, University of Munich, München, Germany

* Corresponding author. Tel: +43 1 4277 55270; fax: +43 1 4277 55969. E-mail address: verena.dirsch{at}univie.ac.at

Aim: Pentoses are widely abundant in organic food. Thermal treatment of pentoses leads to the formation of norfuraneol (NF). The aim of this study was to show whether NF, which is taken up regularly, for example with cooked food, affects the human endothelial nitric oxide synthase (eNOS) system.

Methods and results: The study was performed using cultured human umbilical vein endothelial cells (HUVEC), HUVEC-derived EA.hy926 cells, and bovine aortic endothelial cells. Nitric oxide (NO) release and eNOS activity were measured using diaminofluorescein-2 and [14C]L-arginine/[14C]L-citrulline conversion. Levels of (phospho-)eNOS were detected by western blotting. Reactive oxygen species (ROS) production was assessed using 2',7'-dichlorodihydrofluorescein diacetate. Pharmacokinetic parameters of NF were calculated by VolSurf software. NF dose dependently increased eNOS activity and NO release (30–300 µM), but did not affect total eNOS protein or cellular ROS levels. The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation. Phosphorylation at eNOS-Ser1177 was not significantly altered by NF. Inhibition of protein kinase C with bisindolylmaleimide I (GFX) or calphostin C mimicked the effect of NF. In contrast to GFX, however, NF had no effect on phorbol-12-myristate-13-acetate-induced endothelial ROS formation. In silico, NF is stable towards CYP3A4 metabolism, shows low protein binding, and high tissue distribution.

Conclusion: NF enhances endothelial NO release most likely by promoting specific dephosphorylation of eNOS-Thr495 via PP1 in vitro and may be a promising compound to enhance endothelial function in vivo.

KEYWORDS eNOS; atherosclerosis; endothelium; nitric oxide; hydroxyfuranone; norfuraneol; nutrition

Time for primary review: 17 days


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