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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 26, 2008
Cardiovascular Research, 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 University of Vienna, Department of Pharmacognosy, Althanstraße 14, 1090 Vienna, Austria
2 University of Perugia, Department of Chemistry, Laboratory for Chemometrics and Chemoinformatics, 06123 Perugia, Italy
3 University of Munich, Department of Pharmacy, Butenandtstraße 5-13, 81377 München, Germany

* Corresponding author: Verena M. Dirsch, University of Vienna, Department of Pharmacognosy, Althanstraße 14, 1090 Vienna, Austria, Tel.: +43-1-4277-55270, Fax: +43-1-4277-55969, E-mail: verena.dirsch{at}univie.ac.at

Aim: Pentoses are widely abundant in organic food. Thermal treatment of pentoses leads to 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: The study was performed using cultured human umbilical vein endothelial cells (HUVEC), HUVEC derived EA.hy926 cells and bovine aortic endothelial cells (BAoEC). 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 H2DCF-DA. Pharmacokinetic parameters of NF were calculated by VolSurf software.

Results: 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, tautomyecetin 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, 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.

Time for primary review: 17 Days


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